Ppar active compounds

ABSTRACT

Compounds are described that are active on PPARs, including pan-active compounds. Also described are methods for developing or identifying compounds having a desired selectivity profile.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 11/679,738, filed Feb. 27, 2007, which is a continuation ofU.S. patent application Ser. No. 10/893,134, filed Jul. 16, 2004, whichclaims the benefit of U.S. Provisional Application No. 60/488,523, filedJul. 17, 2003, and U.S. Provisional Application No. 60/552,994, filedMar. 12, 2004, all entitled PPAR Active Compounds, and all of which areincorporated herein by reference in their entireties and for allpurposes.

BACKGROUND OF THE INVENTION

The present invention relates to the field of agonists for the family ofnuclear receptors identified as peroxisome proliferator-activatedreceptors.

The following description is provided solely to assist the understandingof the reader. None of the references cited or information provided isadmitted to be prior art to the present invention. Each of thereferences cited herein is incorporated by reference in its entirety, tothe same extent as if each reference were individually indicated to beincorporated herein in its entirety.

The peroxisome proliferator-activated receptors (PPARs) form a subfamilyin the nuclear receptor superfamily. Three isoforms, encoded by separategenes, have been identified thus far: PPARγ, PPARα, and PPARδ.

There are two PPARγ isoforms expressed at the protein level in mouse andhuman, γ1 and γ2. They differ only in that the latter has 30 additionalamino acids at its N terminus due to differential promoter usage withinthe same gene, and subsequent alternative RNA processing. PPARγ2 isexpressed primarily in adipose tissue, while PPARγ1 is expressed in abroad range of tissues.

Murine PPARα was the first member of this nuclear receptor subclass tobe cloned; it has since been cloned from humans. PPARα is expressed innumerous metabolically active tissues, including liver, kidney, heart,skeletal muscle, and brown fat. It is also present in monocytes,vascular endothelium, and vascular smooth muscle cells. Activation ofPPARα induces hepatic peroxisome proliferation, hepatomegaly, andhepatocarcinogenesis in rodents. These toxic effects are lost in humans,although the same compounds activate PPARα across species.

Human PPARδ was cloned in the early 1990s and subsequently cloned fromrodents. PPARδ is expressed in a wide range of tissues and cells withthe highest levels of expression found in digestive tract, heart,kidney, liver, adipose, and brain. Thus far, no PPARδ-specific genetargets have been identified.

The PPARs are ligand-dependent transcription factors that regulatetarget gene expression by binding to specific peroxisome proliferatorresponse elements (PPREs) in enhancer sites of regulated genes. PPARspossess a modular structure composed of functional domains that includea DNA binding domain (DBD) and a ligand binding domain (LBD). The DBDspecifically binds PPREs in the regulatory region of PPAR-responsivegenes. The DBD, located in the C-terminal half of the receptor containsthe ligand-dependent activation domain, AF-2. Each receptor binds to itsPPRE as a heterodimer with a retinoid X receptor (RXR). Upon binding anagonist, the conformation of a PPAR is altered and stabilized such thata binding cleft, made up in part of the AF-2 domain, is created andrecruitment of transcriptional co-activators occurs. Coactivatorsaugment the ability of nuclear receptors to initiate the transcriptionprocess. The result of the agonist-induced PPAR-co-activator interactionat the PPRE is an increase in gene transcription. Downregulation of geneexpression by PPARs appears to occur through indirect mechanisms.(Bergen & Wagner, 2002, Diabetes Tech. & Ther., 4:163-174).

The first cloning of a PPAR (PPARα) occurred in the course of the searchfor the molecular target of rodent hepatic peroxisome proliferatingagents. Since then, numerous fatty acids and their derivatives includinga variety of eicosanoids and prostaglandins have been shown to serve asligands of the PPARs. Thus, these receptors may play a central role inthe sensing of nutrient levels and in the modulation of theirmetabolism. In addition, PPARs are the primary targets of selectedclasses of synthetic compounds that have been used in the successfultreatment of diabetes and dyslipidemia. As such, an understanding of themolecular and physiological characteristics of these receptors hasbecome extremely important to the development and utilization of drugsused to treat metabolic disorders. In addition, due to the greatinterest within the research community, a wide range of additional rolesfor the PPARs have been discovered; PPARα and PPARγ may play a role in awide range of events involving the vasculature, includingatherosclerotic plaque formation and stability, thrombosis, vasculartone, angio-genesis, and cancer.

Among the synthetic ligands identified for PPARs are Thiazolidinediones(TZDs). These compounds were originally developed on the basis of theirinsulin-sensitizing effects in animal pharmacology studies.Subsequently, it was found that TZDs induced adipocyte differentiationand increased expression of adipocyte genes, including the adipocytefatty acid-binding protein aP2. Independently, it was discovered thatPPARγ interacted with a regulatory element of the aP2 gene thatcontrolled its adipocyte-specific expression. On the basis of theseseminal observations, experiments were performed that determined thatTZDs were PPARγ ligands and agonists and demonstrate a definitecorrelation between their in vitro PPARγ activities and their in vivoinsulin-sensitizing actions. (Bergen & Wagner, 2002, Diabetes Tech. &Ther., 4:163-174).

Several TZDs, including troglitazone, rosiglitazone, and pioglitazone,have insulin-sensitizing and anti-diabetic activity in humans with type2 diabetes and impaired glucose tolerance. Farglitazar is a very potentnon-TZD PPAR-γ-selective agonist that was recently shown to haveantidiabetic as well as lipid-altering efficacy in humans. In additionto these potent PPARγ ligands, a subset of the non-steroidalantiinflammatory drugs (NSAIDs), including indomethacin, fenoprofen, andibuprofen, have displayed weak PPARγ and PPARα activities. (Bergen &Wagner, 2002, Diabetes Tech. & Ther., 4:163-174).

The fibrates, amphipathic carboxylic acids that have been proven usefulin the treatment of hypertriglyceridemia, are PPARα ligands. Theprototypical member of this compound class, clofibrate, was developedprior to the identification of PPARs, using in vivo assays in rodents toassess lipid-lowering efficacy. (Bergen & Wagner, 2002, Diabetes Tech. &Ther., 4:163-174).

Fu et al., Nature, 2003, 425:9093, demonstrated that the PPARα bindingcompound, oleylethanolamide, produces satiety and reduces body weightgain in mice.

Clofibrate and fenofibrate have been shown to activate PPARα with a10-fold selectivity over PPARγ. Bezafibrate acted as a pan-agonist thatshowed similar potency on all three PPAR isoforms. Wy-14643, the2-arylthioacetic acid analogue of clofibrate, was a potent murine PPARαagonist as well as a weak PPARγ agonist. In humans, all of the fibratesmust be used at high doses (200-1,200 mg/day) to achieve efficaciouslipid-lowering activity.

TZDs and non-TZDs have also been identified that are dual PPARγ/αagonists. By virtue of the additional PPARα agonist activity, this classof compounds has potent lipid-altering efficacy in addition toantihyperglycemic activity in animal models of diabetes and lipiddisorders. KRP-297 is an example of a TZD dual PPARγ/α agonist (Fajas,1997, J. Biol. Chem., 272:18779-18789) DRF-2725 and AZ-242 are non-TZDdual PPARγ/α agonists. (Lohray, et al., 2001, J. Med. Chem.,44:2675-2678; Cronet, et al., 2001, Structure (Camb.) 9:699-706).

In order to define the physiological role of PPARδ, efforts have beenmade to develop novel compounds that activate this receptor in aselective manner. Amongst the α-substituted carboxylic acids previouslydescribed, the potent PPARδ ligand L-165041 demonstrated approximately30-fold agonist selectivity for this receptor over PPARδ; it wasinactive on murine PPARα (Liebowitz, et al., 2000, FEBS Lett.,473:333-336). This compound was found to increase high-densitylipoprotein levels in rodents. It was also reported that GW501516 was apotent, highly-selective PPARγ agonist that produced beneficial changesin serum lipid parameters in obese, insulin-resistant rhesus monkeys.(Oliver et al., 2001, Proc. Natl. Acad. Sci., 98:5306-5311).

In addition to the compounds above, certain thiazole derivatives activeon PPARs have been described. (Cadilla et al., Internat. Appl.PCT/US01/149320, Internat. Publ. W) 02/062774, incorporated herein byreference in its entirety.)

Some tricyclic-α-alkyloxyphenylpropionic acids were described as dualPPARα/γ agonists. Sauerberg et al., 2002, J. Med. Chem. 45:789-804.)

A group of compounds that were stated to have equal activity onPPARα/γ/δ was described in Morgensen et al., 2002, Bioorg. & Med. Chem.Lett. 13:257-260.

Oliver et al., described a selective PPARδ agonist that promotes reversecholesterol transport. (Oliver et al., 2001, PNAS 98:5306-5311.)

Yamamoto et al., U.S. Pat. No. 3,489,767 describes“1-(phenylsulfonyl)-indolyl aliphatic acid derivatives” that are statedto have “antiphlogistic, analgesic and antipyretic actions.” (Col. 1,lines 16-19.)

Kato et al., European patent application 94101551.3, Publication No. 0610 793 A1, describes the use of3-(5-methoxy-1-p-toluenesulfonylindol-3-yl)propionic acid (page 6) and1-(2,3,6-triisopropylphenylsulfonyl)-indole-3-propionic acid (page 9) asintermediates in the synthesis of particular tetracyclic morpholinederivatives.

SUMMARY OF THE INVENTION

In the present invention, compounds were identified that were onlyweakly active on PPARs. Identification of such compounds led to theidentification of molecular scaffolds that allows for convenient liganddevelopment utilizing structural information about the PPARS, and thepreparation of compounds based on that scaffold that have greatlyenhanced activity on PPARs as compared to the compounds initiallyidentified. Included are compounds that have significant pan-activityacross the PPARs, PPARα, PPARδ, and PPARγ, as well as compounds thathave significant specificity (at least 5-, 10-, or 20-fold greateractivity) on a single PPAR, or on two of the three PPARs.

A molecular scaffold is represented below by the structure of Formula I,but with n=1, Y═CH, the R substituents except for R¹ as H, and with R¹as —COOH. Similar scaffolds with each of the alternate selections forthe indicated moieties (e.g., Y═N and/or n=0 or 2 and/or R¹ as one ofthe other indicated substituents) are also provided. The presentinvention concerns molecular scaffolds of Formula I and the use of suchmolecular scaffolds, and the use of compounds with the structure ofFormula I as modulators of the PPARs, PPARα, PPARδ, and PPARγ, whereFormula I is:

where:

U, V, W, X, and Y are independently substituted N or CR⁸, where thereare no more than 4, and preferably no more than 3, nitrogens in thebicyclic ring structure shown in Formula I, and there are no more than 2nitrogens in either of the rings;

R¹ is a carboxyl group (or ester thereof) or a carboxylic acid isosteresuch as optionally substituted thiazolidine dione, optionallysubstituted hydroxamic acid, optionally substituted acyl-cyanamide,optionally substituted tetrazole, optionally substituted isoxazole,optionally substituted sulphonate, optionally substituted sulfonamide,and optionally substituted acylsulphonamide;

R² is hydrogen, optionally substituted lower alkyl, —CH₂—CR¹²═CR¹³R¹⁴,—CH₂—C≡CR¹⁵, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, optionally substitutedheteroaralkyl, —C(Z)NR R¹¹, —C(Z)R²⁰, —S(O)₂NR¹⁰R¹¹; or —S(O)₂R²¹;

R⁶ and R⁷ are independently hydrogen, optionally substituted loweralkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, or optionally substitutedheteroaralkyl, or R⁶ and R⁷ combine to form a mono-carbocyclic ormono-heterocyclic 5- or 6-membered ring system;

R⁸ is hydrogen, halo, optionally substituted lower alkyl,—CH₂—CR¹²═CR¹³R¹⁴, optionally substituted cycloalkyl, optionallysubstituted monofluoroalkyl, optionally substituted difluoroalkyl,optionally substituted trifluoroalkyl, trifluoromethyl, —CH₂—C≡CR¹⁵,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heteroaryl,optionally substituted heteroaralkyl, —OR⁹, —SR⁹, —C(Z)NR¹⁰R¹¹,—C(Z)R²⁰, —S(O)₂NR¹⁰R¹¹, or —S(O)₂R²¹;

R⁹ is optionally substituted lower alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, or optionally substituted heteroaralkyl;

R¹⁰ and R¹¹ are independently hydrogen, optionally substituted loweralkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, or optionally substitutedheteroaralkyl, or R¹⁰ and R¹¹ combine to form a mono-carbocyclic ormono-heterocyclic 5- or 6-membered ring system;

R¹², R¹³, R¹⁴, and R¹⁵ are independently optionally substituted loweralkyl, optionally substituted cycloalkyl, optionally substitutedmonofluoroalkyl, trifluoromethyl, optionally substituted difluoroalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heteroaryl, oroptionally substituted heteroaralkyl;

R²⁰ is optionally substituted monofluoroalkyl, trifluoromethyl,optionally substituted difluoroalkyl, —CH₂—CR¹²═CR¹³R¹⁴, —CH₂—C≡CR¹⁵,optionally substituted lower alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heteroaryl, oroptionally substituted heteroaralkyl;

R²¹ is optionally substituted lower alkoxy, —CH₂—CR¹²CR¹³R¹⁴,—CH₂—C≡CR¹⁵, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, or optionally substitutedheteroaralkyl;

Z is O or S; and

n=0, 1, or 2.

In specifying a compound or compounds of Formula I, unless indicated tothe contrary, specification of such compound(s) includespharmaceutically acceptable salts of the compound(s).

In connection with compounds of Formula I, various chemical structuresand moieties have the following meanings

“Halo” or “Halogen”—alone or in combination means all halogens, that is,chloro (Cl), fluoro (F), bromo (Br), iodo (I).

“Hydroxyl” refers to the group —OH.

“Thiol” or “mercapto” refers to the group —SH.

“Alkyl”—alone or in combination means an alkane-derived radicalcontaining from 1 to 20, preferably 1 to 15, carbon atoms (unlessspecifically defined). It is a straight chain alkyl, branched alkyl, orcycloalkyl. In many embodiments, an alkyl is a straight or branchedalkyl group containing from 1-15, 1 to 8, 1-6, 1-4, or 1-2, carbonatoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl and thelike. The term “lower alkyl” is used herein to describe the straightchain alkyl groups of 1-6, 1-4, or 1-2 carbon atoms. Preferably,cycloalkyl groups are monocyclic, bicyclic or tricyclic ring systems of3-8, more preferably 3-6, ring members per ring, such as cyclopropyl,cyclopentyl, cyclohexyl, and the like, but can also include larger ringstructures such as adamantyl. Alkyl also includes a straight chain orbranched alkyl group that contains or is interrupted by a cycloalkylportion. The straight chain or branched alkyl group is attached at anyavailable point to produce a stable compound. Examples of this include,but are not limited to, 4-(isopropyl)-cyclohexylethyl or2-methyl-cyclopropylpentyl. A substituted alkyl is a straight chainalkyl, branched alkyl, or cycloalkyl group defined previously,independently substituted with 1 to 3 groups or substituents of halo,hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy,aryloxy, heteroaryloxy, amino optionally mono- or di-substituted withalkyl, aryl or heteroaryl groups, amidino, urea optionally substitutedwith alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyloptionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroarylgroups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino,alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or thelike.

“Alkenyl”—alone or in combination means a straight, branched, or cyclichydrocarbon containing 2-20, preferably 2-17, more preferably 2-10, evenmore preferably 2-8, most preferably 2-4, carbon atoms and at least one,preferably 1-3, more preferably 1-2, most preferably one, carbon tocarbon double bond. In the case of a cycloalkenyl group, conjugation ofmore than one carbon to carbon double bond is not such as to conferaromaticity to the ring. Carbon to carbon double bonds may be eithercontained within a cycloalkenyl portion, with the exception ofcyclopropenyl, or within a straight chain or branched portion. Examplesof alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl,cyclohexenyl, cyclohexenylalkyl and the like. A substituted alkenyl isthe straight chain alkenyl, branched alkenyl or cycloalkenyl groupdefined previously, independently substituted with 1 to 3 groups orsubstituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono-or di-substituted with alkyl, aryl or heteroaryl groups, amidino, ureaoptionally substituted with alkyl, aryl, heteroaryl or heterocyclylgroups, aminosulfonyl optionally N-mono- or N,N-di-substituted withalkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino,heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino,heteroarylcarbonylamino, carboxy, alkoxycarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, or the like attached at any available point toproduce a stable compound.

“Alkynyl”—alone or in combination means a straight or branchedhydrocarbon containing 2-20, preferably 2-17, more preferably 2-10, evenmore preferably 2-8, most preferably 2-4, carbon atoms containing atleast one, preferably one, carbon to carbon triple bond. Examples ofalkynyl groups include ethynyl, propynyl, butyryl and the like. Asubstituted alkynyl refers to the straight chain alkynyl or branchedalkynyl defined previously, independently substituted with 1 to 3 groupsor substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono-or di-substituted with alkyl, aryl or heteroaryl groups, amidino, ureaoptionally substituted with alkyl, aryl, heteroaryl or heterocyclylgroups, aminosulfonyl optionally N-mono- or N,N-di-substituted withalkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino,heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino,heteroarylcarbonylamino, or the like attached at any available point toproduce a stable compound.

“Alkyl alkenyl” refers to a group —R—CR′═CR′″R″″, where R is loweralkylene, or substituted lower alkylene, R′, R′″, R″″ may independentlybe hydrogen, halogen, lower alkyl, substituted lower alkyl, acyl, aryl,substituted aryl, hetaryl, or substituted hetaryl as defined below.

“Alkyl alkynyl” refers to a groups —RCCR′ where R is lower alkylene orsubstituted lower alkylene, R′ is hydrogen, lower alkyl, substitutedlower alkyl, acyl, aryl, substituted aryl, hetaryl, or substitutedhetaryl as defined below.

“Alkoxy” denotes the group —OR, where R is lower alkyl, substitutedlower alkyl, acyl, aryl, substituted aryl, aralkyl, substituted aralkyl,heteroalkyl, heteroarylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, or substituted cycloheteroalkyl as defined.

“Alkylthio” or “thioalkoxy” denotes the group —SR, —S(O)_(n=1-2)—R,where R is lower alkyl, substituted lower alkyl, aryl, substituted aryl,aralkyl or substituted aralkyl as defined herein.

“Acyl” denotes groups —C(O)R, where R is hydrogen, lower alkyl,substituted lower alkyl, aryl, substituted aryl and the like as definedherein.

“Aryloxy” denotes groups —OAr, where Ar is an aryl, substituted aryl,heteroaryl, or substituted heteroaryl group as defined herein.

“Amino” or substituted amine denotes the group —NRR′, where R and R′ mayindependently by hydrogen, lower alkyl, substituted lower alkyl, aryl,substituted aryl, hetaryl, or substituted heteroaryl as defined herein,acyl or sulfonyl.

“Amido” denotes the group —C(O)NRR′, where R and R′ may independently byhydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl,hetaryl, substituted hetaryl as defined herein.

“Carboxyl” denotes the group —C(O)OR, where R is hydrogen, lower alkyl,substituted lower alkyl, aryl, substituted aryl, hetaryl, andsubstituted hetaryl as defined herein.

The term “carboxylic acid isostere” refers to a group selected fromoptionally substituted thiazolidine dione, optionally substitutedhydroxamic acid, optionally substituted acyl-cyanamide, optionallysubstituted tetrazole, optionally substituted isoxazole, optionallysubstituted sulphonate, optionally substituted sulfonamide, andoptionally substituted acylsulphonamide

“Carbocyclic” refers to a saturated, unsaturated, or aromatic grouphaving a single ring (e.g., phenyl) or multiple condensed rings whereall ring atoms are carbon atoms, which can optionally be unsubstitutedor substituted with, e.g., halogen, lower alkyl, lower alkoxy,alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy,heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol,sulfamido and the like.

“Aryl”—alone or in combination means phenyl or naphthyl optionallycarbocyclic fused with a cycloalkyl of preferably 5-7, more preferably5-6, ring members and/or optionally substituted with 1 to 3 groups orsubstituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono-or di-substituted with alkyl, aryl or heteroaryl groups, amidino, ureaoptionally substituted with alkyl, aryl, heteroaryl or heterocyclylgroups, aminosulfonyl optionally N-mono- or N,N-di-substituted withalkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino,heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino,heteroarylcarbonylamino, or the like.

“Substituted aryl” refers to aryl optionally substituted with one ormore functional groups, e.g., halogen, lower alkyl, lower alkoxy,alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy,heterocycle, heteroaryl, substituted heteroaryl, nitro, cyano, thiol,sulfamido and the like.

“Heterocycle” refers to a saturated, unsaturated, or aromatic grouphaving a single ring (e.g., morpholino, pyridyl or furyl) or multiplecondensed rings (e.g., naphthpyridyl, quinoxalyl, quinolinyl,indolizinyl or benzo[b]thienyl) and having carbon atoms and at least onehetero atom, such as N, O or S, within the ring, which can optionally beunsubstituted or substituted with, e.g., halogen, lower alkyl, loweralkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl,aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol,sulfamido and the like.

“Heteroaryl”—alone or in combination means a monocyclic aromatic ringstructure containing 5 or 6 ring atoms, or a bicyclic aromatic grouphaving 8 to 10 atoms, containing one or more, preferably 1-4, morepreferably 1-3, even more preferably 1-2, heteroatoms independentlyselected from the group O, S, and N, and optionally substituted with 1to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, aminooptionally mono- or di-substituted with alkyl, aryl or heteroarylgroups, amidino, urea optionally substituted with alkyl, aryl,heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- orN,N-di-substituted with alkyl, aryl or heteroaryl groups,alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino,alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or thelike. Heteroaryl is also intended to include oxidized S or N, such assulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon ornitrogen atom is the point of attachment of the heteroaryl ringstructure such that a stable aromatic ring is retained. Examples ofheteroaryl groups are pyridinyl, pyridazinyl, pyrazinyl, quinazolinyl,purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, oxazolyl,thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl,tetrazolyl, imidazolyl, triazinyl, furanyl, benzofuryl, indolyl and thelike. A substituted heteroaryl contains a substituent attached at anavailable carbon or nitrogen to produce a stable compound.

“Heterocyclyl”—alone or in combination means a non-aromatic cycloalkylgroup having from 5 to 10 atoms in which from 1 to 3 carbon atoms in thering are replaced by heteroatoms of O, S or N, and are optionally benzofused or fused heteroaryl of 5-6 ring members and/or are optionallysubstituted as in the case of cycloalkyl. Heterocycyl is also intendedto include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of atertiary ring nitrogen. The point of attachment is at a carbon ornitrogen atom. Examples of heterocyclyl groups are tetrahydrofuranyl,dihydropyridinyl, piperidinyl, pyrrolidinyl, piperazinyl,dihydrobenzofuryl, dihydroindolyl, and the like. A substitutedheterocyclyl group contains a substituent nitrogen attached at anavailable carbon or nitrogen to produce a stable compound.

“Substituted heteroaryl” refers to a heterocycle optionally mono or polysubstituted with one or more functional groups, e.g., halogen, loweralkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl,hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl,substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

“Aralkyl” refers to the group —R—Ar where Ar is an aryl group and R islower alkyl or substituted lower alkyl group. Aryl groups can optionallybe unsubstituted or substituted with, e.g., halogen, lower alkyl,alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl,aryloxy, heterocycle, substituted heterocycle, hetaryl, substitutedhetaryl, nitro, cyano, thiol, sulfamido and the like.

“Heteroalkyl” refers to the group —R-Het where Het is a heterocyclegroup and R is a lower alkylene group. Heteroalkyl groups can optionallybe unsubstituted or substituted with e.g., halogen, lower alkyl, loweralkoxy, alkylthio, acetylene, amino, amido, carboxyl, aryl, aryloxy,heterocycle, substituted heterocycle, hetaryl, substituted hetaryl,nitro, cyano, thiol, sulfamido and the like.

“Heteroarylalkyl” refers to the group —R-HetAr where HetAr is anheteroaryl group and R is lower alkylene or substituted lower alkylene.Heteroarylalkyl groups can optionally be unsubstituted or substitutedwith, e.g., halogen, lower alkyl, substituted lower alkyl, alkoxy,alkylthio, acetylene, aryl, aryloxy, heterocycle, substitutedheterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol,sulfamido and the like.

“Cycloalkyl” refers to a cyclic or polycyclic alkyl group containing 3to 15 carbon atoms.

“Substituted cycloalkyl” refers to a cycloalkyl group comprising one ormore substituents with, e.g., halogen, lower alkyl, substituted loweralkyl, alkoxy, alkylthio, acetylene, aryl, aryloxy, heterocycle,substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano,thiol, sulfamido and the like.

“Cycloheteroalkyl” refers to a cycloalkyl group wherein one or more ofthe ring carbon atoms is replaced with a heteroatom (e.g., N, O, S orP).

Substituted cycloheteroalkyl” refers to a cycloheteroalkyl group asherein defined which contains one or more substituents, such as halogen,lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl,hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl,substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

“Alkyl cycloalkyl” denotes the group —R-cycloalkyl where cycloalkyl is acycloalkyl group and R is a lower alkylene or substituted loweralkylene. Cycloalkyl groups can optionally be unsubstituted orsubstituted with e.g. halogen, lower alkyl, lower alkoxy, alkylthio,acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle,substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano,thiol, sulfamido and the like.

“Alkyl cycloheteroalkyl” denotes the group —R-cycloheteroalkyl where Ris a lower alkylene or substituted lower alkylene. Cycloheteroalkylgroups can optionally be unsubstituted or substituted with e.g. halogen,lower alkyl, lower alkoxy, alkylthio, amino, amido, carboxyl, acetylene,hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl,substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

In certain embodiments involving compounds of Formula I, the compoundshave a structure of Formula I in which the bicyclic core shown forFormula I has one of the following structures:

Thus, in particular embodiments involving compounds of Formula I, thecompound includes a bicyclic core as shown above. Such compounds caninclude substitutents as described for Formula I, with the understandingthat ring nitrogens other than the nitrogen corresponding to position 1of the indole structure are unsubstituted. In particular embodiments,the compounds have one of the bicyclic cores shown above andsubstitution selections as shown herein for compounds having an indolylcore; the compounds have one of the bicyclic cores above, and thesubstituents shown at the 5-position are instead attached at the6-position.

In certain embodiments involving compounds of Formula I, the compoundshave a structure of Formula I-1, namely

where:

R³, R⁴, and R⁵ are independently hydrogen, halo, trifluoromethyl,optionally substituted lower alkyl, —CH₂—CR¹²═CR¹³R¹⁴, optionallysubstituted monofluoroalkyl, optionally substituted difluoroalkyl,optionally substituted trifluoroalkyl, —CH₂—C≡CR¹⁵, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heteroaryl, optionally substituted heteroaralkyl, —OR⁹,—SR⁹, —C(Z)NR¹⁰R¹¹, —C(Z)R²⁰, —S(O)₂NR¹⁰R¹¹, or —S(O)₂R²¹.

In particular embodiments of the different aspects of the invention,including in certain embodiments, the compounds of Formula I arecompounds of Formulas Ia, Ib, Ic, Id, X, or XIV as shown in the DetailedDescription. Also in particular embodiments, such compounds arecompounds of Formula I with Y═N; with Y═CR⁸; with Y═CH; with all Rsubstituents other than R¹, R², and R⁴ as H (for each of X as N, X asCH, and X as CR⁸); with R⁶ and R⁷ as H (for each of X as N, X as CH, andX as CR⁸).

In certain embodiments, n=1; n=1 and X and/or Y is CH; n=1, X and/or Yis CH, and R⁶ and R⁷ are H; n=1 and X and/or Y═CR⁸.

In certain embodiments, n=1, R² is —S(O)₂R²¹, with R²¹ being optionallysubstituted aryl or optionally substituted heteroaryl. In certainembodiments, in which n=1, and R² is —S(O)₂R²¹, with R²¹ beingoptionally substituted aryl or optionally substituted heteroaryl, thearyl group is a 5- or 6-membered ring; the aryl group is a 6-memberedring; in further embodiments in which the aryl group is a 6-memberedring, the ring is substituted with one or two groups independentlyselected from halo, alkoxy, cycloalkyl, aryl, aryloxy, heteroaryl,heteroaryloxy, aryl or heteroaryl substituted alkyl, and aryl orheteroaryl substituted alkoxy; in further embodiments in which a6-membered ring is substituted with halo or alkoxy, the ring issubstituted at the 3-position (meta), 4-position (para), or 3- and4-positions (meta and para); in further embodiments in which a6-membered ring is substituted at the 4-position, or 3- and 4-positions,the 4-position substitutent is lower alkyl, the 4-position substituentis not alkyl, the 4-position substituent is halo (e.g., fluoro orchloro), the 3- and 4-position substituents are fluoro, the 3- and4-position substitutents are chloro, one of the 3- and 4-positionsubstituents is fluoro and the other is chloro, the 3-position is halo(e.g., fluoro or chloro) and the 4-position is alkoxy (e.g., methoxy orethoxy), the 3-position is alkoxy (e.g., methoxy or ethoxy) and the4-position is halo (e.g., fluoro or chloro), the 3-position is chloroand the 4-position is alkoxy, the 3-position is alkoxy and the4-position is chloro; the 6-membered ring is fused with a second 5- or6-membered aromatic or non-aromatic carbocyclic or heterocyclic ring. Infurther embodiments in which the aryl group is a 5-membered ring, thering is substituted with one or two groups located at ring positions notadjacent to the ring atom linked to the —S(O)₂— group; the 5-memberedring is substituted with one or two ring substituents selected from thegroup consisting of halo, alkoxy, cycloalkyl, aryl, aryloxy, heteroaryl,heteroaryloxy, aryl or heteroaryl substituted alkyl, and aryl orheteroaryl substituted alkoxy; the ring is substituted with chloro; thering is substituted with alkoxy; the ring is substituted with alkyl; thering is substituted with optionally substituted aryl or heteroaryl; thering is substituted with optionally substituted aryloxy orheteroaryloxy; the 5-membered ring is fused with a second 5- or6-membered aromatic or non-aromatic carbocyclic or heterocyclic ring.

In certain embodiments in which n=1, and R² is —S(O)₂R²¹, with R²¹ beingoptionally substituted aryl or optionally substituted heteroaryl, R⁴ isdifferent from H and alkoxy, or R⁴ is different from H and OR⁹.

In certain embodiments, n=2; n=2 and X and/or Y is CH; n=2, X and/or Yis CH, and R⁶ and R⁷ are H; n=2 and X and/or Y is CR⁸; n=2 and X and/orY is N.

In certain embodiments in which n=2, R⁴ is different from H, halo,alkyl, alkoxy, alkylthio; R⁴ is different from H, halo, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₃ alkylthio; R⁴ is different from C₁₋₃ alkoxy; R⁴ is notmethoxy.

In certain embodiments, n=2, R² is —S(O)₂R²¹, with R²¹ being optionallysubstituted aryl or optionally substituted heteroaryl. In certainembodiments, in which n=2, and R² is —S(O)₂R²¹, with R²¹ beingoptionally substituted aryl or optionally substituted heteroaryl, thearyl group is a 5- or 6-membered ring; the aryl group is a 6-memberedring; in further embodiments in which the aryl group is a 6-memberedring, the ring is substituted with one or two groups independentlyselected from halo, alkyl, cycloalkyl, aryl, aryloxy, heteroaryl,heteroaryloxy, aryl or heteroaryl substituted alkyl, and aryl orheteroaryl substituted alkoxy; in further embodiments in which a6-membered ring is substituted with halo or alkoxy, the ring issubstituted at the 3-position (meta), 4-position (para), or 3- and4-positions (meta and para); in further embodiments in which a6-membered ring is substituted at the 4-position, or 3- and 4-positions,the 4-position substitutent is lower alkyl, the 4-position substituentis not alkyl, the 4-position substituent is halo (e.g., fluoro orchloro), the 3- and 4-position substituents are fluoro, the 3- and4-position substitutents are chloro, one of the 3- and 4-positionsubstituents is fluoro and the other is chloro, the 3-position is halo(e.g., fluoro or chloro) and the 4-position is alkoxy (e.g., methoxy orethoxy), the 3-position is alkoxy (e.g., methoxy or ethoxy) and the4-position is halo (e.g., fluoro or chloro), the 3-position is chloroand the 4-position is alkoxy, the 3-position is alkoxy and the4-position is chloro; the 6-membered ring is fused with a second 5- or6-membered aromatic or non-aromatic carbocyclic or heterocyclic ring. Infurther embodiments in which the aryl group is a 5-membered ring, thering is substituted with one or two groups located at ring positions notadjacent to the ring atom linked to the —S(O)₂— group; the 5-memberedring is substituted with one or two ring substituents selected from thegroup consisting of halo, alkoxy, cycloalkyl, aryl, aryloxy, heteroaryl,heteroaryloxy, aryl or heteroaryl substituted alkyl, and aryl orheteroaryl substituted alkoxy; the ring is substituted with chloro; thering is substituted with alkoxy; the ring is substituted with alkyl; thering is substituted with optionally substituted aryl or heteroaryl; thering is substituted with optionally substituted aryloxy orheteroaryloxy; the 5-membered ring is fused with a second 5- or6-membered aromatic or non-aromatic carbocyclic or heterocyclic ring.

In certain embodiments, in which n=2, and R² is —S(O)₂R²¹, with R²¹being a substituted aryl group with a 6-membered, the substitution onthe aryl group is not methoxy, the substitution on the aryl group is notalkoxy; the substitution on the aryl group is not alkoxy; R⁴ and thesubstitution on the aryl group are not both alkoxy; R⁴ and thesubstitution on the aryl group are not both methoxy; R⁴ is not alkoxy;R⁴ is not methoxy.

Certain further embodiments include compounds described forcorresponding embodiments as described above for both n=1 and n=2.

In certain embodiments, compounds of Formula I have a structure ofFormula Ie as shown below:

where

R⁴ is hydrogen, halo, optionally substituted lower alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heteroaryl, optionally substituted heteroaralkyl, —OR⁹(e.g., optionally substituted alkoxy, for example, methoxy, ethoxy)—SR⁹, —NR¹⁰R¹¹, —C(Z)NR¹⁰R¹¹, —C(Z)R²⁰, °S(O)₂NR¹⁰R¹¹, or —S(O)₂R²¹;

R²⁴ is H, halo, optionally substituted alkyl, optionally substitutedalkoxy, or optionally substituted aryloxy, or optionally substitutedaralkoxy (e.g., Aryl-O(CH₂)_(p)O—, where p is 1-4);

R²⁵ is H, halo, optionally substituted alkyl, optionally substitutedalkoxy, optionally substituted aryloxy, or R²⁴ and R²⁵ together form afused ring with the phenyl group, e.g., benzofuran.

In particular embodiments, R⁴ is optionally substituted alkoxy (e.g.,methoxy, ethoxy, propoxy, isopropoxy), optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted alkyl(e.g., methyl or ethyl), optionally substituted cycloalkyl, optionallysubstituted cycloheteroalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, or halo.

In particular embodiments, R⁴ is optionally substituted alkoxy (e.g.,methoxy, ethoxy, propoxy, isopropoxy), optionally substituted alkyl(e.g., methyl or ethyl), optionally substituted aryl, optionallysubstituted heteroaryl, or halo.

In particular embodiments, compounds of Formula I can be as specifiedfor Formula Ie, but with the phenyl ring to which R²⁴ and R²⁵ areattached as a heteroaryl ring. If the heteroaryl ring is a 5-memberedring, R²⁴ and R²⁵ are attached at the ring positions that are notadjacent to the atom linking to the sulfonyl group shown in Formula Ie.

In particular embodiments of compounds of Formula Ie, R⁴ is alkoxy andR²⁴ and R²⁵ are chloro; R⁴ is alkoxy and R²⁴ and R²⁵ are fluoro; R⁴ isalkoxy and R²⁴ is alkoxy; R⁴ is alkoxy and R²⁴ is alkyl; R⁴ is methoxyor ethoxy and R²⁴ and R²⁵ are chloro; R⁴ is methoxy or ethoxy and R²⁴ isalkoxy; R⁴ is methoxy or ethoxy and R²⁴ is alkyl.

In particular embodiments of compounds of Formula Ie, both of R²⁴ andR²⁵ are not alkyl; neither of R²⁴ and R²⁵ are alkyl; with R²⁴ as H, R²⁵is not alkyl; with R²⁵ as H, R²⁴ is not alkyl.

Exemplary compounds include those listed in Table 1 and in Table 4.Reference to compounds of Formula I herein includes specific referenceto sub-groups and species of compounds of Formula I described herein(e.g., particular embodiments as described above) unless indicated tothe contrary.

In particular embodiments, any one or more of the sub-groups ofcompounds of Formula I or any one or more of the exemplary compounds isexcluded from one of the specified compound groups or sub-groups ofFormula I that would otherwise include such sub-group or sub-groups.

In particular embodiments of aspects involving compounds of Formula I,the compound is specific for PPARα; specific for PPARδ; specific forPPARγ; specific for PPARα and PPARδ; specific for PPARα, and PPARγ;specific for PPARδ and PPARγ. Such specificity means that the compoundhas at least 5-fold greater activity (preferably at least 1-, 20-, 50-,or 100-fold or more greater activity) on the specific PPAR(s) than onthe other PPAR(s), where the activity is determined using a biochemicalassay suitable for determining PPAR activity, e.g., an assay asdescribed herein.

A first aspect of the invention concerns novel compounds of Formula Iand sub-groups of Formula I, e.g., as described above or otherwisedescribed herein.

A related aspect of this invention concerns pharmaceutical compositionsthat include a compound of Formula I and at least one pharmaceuticallyacceptable carrier, excipient, or diluent. The composition can include aplurality of different pharmacalogically active compounds.

In another related aspect, compounds of Formula I can be used in thepreparation of a medicament for the treatment of a PPAR-mediated diseaseor condition.

In another aspect, the invention concerns a method of treating orprophylaxis of a disease or condition in a mammal, by administering tothe mammal a therapeutically effective amount of a compound of FormulaI, a prodrug of such compound, or a pharmaceutically acceptable salt ofsuch compound or prodrug. The compound can be alone or can be part of apharmaceutical composition.

In aspects and embodiments involving treatment or prophylaxis of adisease or conditions, the disease or condition is obesity, overweightcondition, hyperlipidemia, dyslipidemia including associated diabeticdyslipidemia and mixed dyslipidemia, hypoalphalipoproteinemia, SyndromeX, Type II diabetes mellitus, Type I diabetes, hyperinsulinemia,impaired glucose tolerance, insulin resistance, a diabetic complication(e.g., neuropathy, nephropathy, retinopathy or cataracts), hypertension,coronary heart disease, heart failure, hypercholesterolemia,inflammation, thrombosis, congestive heart failure, cardiovasculardisease (including atherosclerosis, arteriosclerosis, andhypertriglyceridemia), epithelial hyperproliferative diseases (such aseczema and psoriasis), cancer, and conditions associated with the lungand gut and regulation of appetite and food intake in subjects sufferingfrom disorders such as obesity, anorexia bulimia and anorexia nervosa.

The identification of compounds of Formula I active on PPARs alsoprovides a method for identifying or developing additional compoundsactive on PPARs, e.g., improved modulators, by determining whether anyof a plurality of test compounds of Formula I active on at least onePPAR provides an improvement in one or more desired pharmacologicproperties relative to a reference compound active on such PPAR, andselecting a compound If any, that has an improvement in the desiredpharmacologic property, thereby providing an improved modulator.

In particular embodiments of aspects of modulator development, thedesired pharmacologic property is PPAR pan-activity, PPAR selectivityfor any individual PPAR (PPARα, PPARδ, or PPARγ), selectivity on any twoPPARs (PPARα and PPARδ, PPARα and PPARγ, or PPARδ and PPARγ), serumhalf-life longer than 2 hr or longer than 4 hr or longer than 8 hr,aqueous solubility, oral bioavailability more than 10%, oralbioavailability more than 20%.

Also in particular embodiments of aspects of modulator development, thereference compound is a compound of Formula I. The process can berepeated multiple times, i.e., multiple rounds of preparation ofderivatives and/or selection of additional related compounds andevaluation of such further derivatives of related compounds, e.g., 1, 2,3, 4, 5, 6, 7, 8, 9, 10 or more additional rounds.

In additional aspects, structural information about one or more of thePPARs is utilized, e.g., in conjunction with compounds of Formula I or amolecular scaffold or scaffold core of Formula I.

Thus, in another aspect, the invention provides a method of designing aligand that binds to at least one member of the PPAR protein family(PPARα, PPARδ, and PPARγ), by identifying as molecular scaffolds one ormore compounds that bind to a binding site of a PPAR with low affinity;determining the orientation of the one or more molecular scaffolds atthe binding site of the PPAR by obtaining co-crystal structures of themolecular scaffolds in the binding site; identifying one or morestructures of at least one scaffold molecule that, when modified,provide a ligand having altered binding affinity or binding specificityor both for binding to the PPAR as compared to the binding of thescaffold molecule. The designed ligand(s) can then be provided, e.g., bysynthesizing or otherwise obtaining the ligand(s). In particularembodiments, the molecular scaffold is a compound of Formula I, orcontains a bicyclic core as shown above for Formula I.

In particular embodiments, a plurality of distinct compounds are assayedfor binding to the binding site of the PPAR; co-crystals of themolecular scaffolds bound to the PPAR are isolated, and the orientationof the molecular scaffold is determined by performing X-raycrystallography on the co-crystals; the method further involvesidentifying common chemical structures of the molecular scaffolds,placing the molecular scaffolds into groups based on having at least onecommon chemical structure, and determining the orientation of the one ormore molecular scaffolds at the binding site of the PPAR for at leastone representative compound from a plurality of groups; the ligand bindsto the target molecule with greater binding affinity or greater bindingspecificity or both than the molecular scaffold; the orientation of themolecular scaffold is determined by nuclear magnetic resonance inco-crystal structure determination; the plurality of distinct compoundsare each assayed for binding to a plurality of members of the PPARfamily.

Also in particular embodiments, after the identification of commonchemical structures of the distinct compounds that bind, the compoundsare grouped into classes based on common chemical structures and arepresentative compound from a plurality of the classes is selected forperforming X-ray crystallography on co-crystals of the compound andtarget molecule; the distinct compounds are selected based on criteriaselected from molecular weight, clogP, and the number of hydrogen bonddonors and acceptors; the clog P is less than 2, and the number ofhydrogen bond donors and acceptors is less than 5.

In certain embodiments, the distinct compounds have a molecular weightof from about 100 to about 350 daltons, or more preferably from about150 to about 350 daltons or from 150 to 300 daltons, or from 200 to 300daltons. The distinct compounds can be of a variety of structures. Insome embodiments, the distinct compounds can have a ring structure,either a carbocyclic or heterocyclic ring, such as for example, a phenylring, a pyrrole, imidazole, pyridine, purine, or any ring structure.

In various embodiments, a compound or compounds binds with extremely lowaffinity, very low affinity, low affinity, moderate affinity, or highaffinity; at least about 5% of the binding compounds bind with lowaffinity (and/or has low activity), or at least about 10%, 15%, or 20%of the compounds bind with low affinity (or very low or extremely low).After the identification of common chemical structures of the distinctcompounds that bind, the compounds can be grouped into classes based oncommon chemical structures and at least one representative compound fromat least one, or preferably a plurality, of the classes selected forperforming orientation determination, e.g., by X-ray crystallographyand/or NMR analysis.

In selecting the distinct compounds for assay in the present invention,the selection can be based on various criteria appropriate for theparticular application, such as molecular weight, clogP (or other methodof assessing lipophilicity), Polar Surface Area (PSA) (or otherindicator of charge and polarity or related properties), and the numberof hydrogen bond donors and acceptors. Compounds can also be selectedusing the presence of specific chemical moieties which, based oninformation derived from the molecular family, might be indicated ashaving predisposing some affinity for members of the family. Compoundswith highly similar structures and/or properties can be identified andgrouped using computational techniques to facilitate the selection of arepresentative subset of the group. As indicated above, in preferredembodiments, the molecular weight is from about 150 to about 350daltons, more preferably from 150 to 300 daltons. The clog P ispreferably less than 2, the number of hydrogen bond donors and acceptorsis preferably less than 5 and the PSA less than 100. Compounds can beselected that include chemical structures of drugs having acceptablepharmacalogical properties and/or lacking chemical strutures that areknown to result in undesirable pharmacological properties, e.g.,excessive toxicity and lack of solubility.

In some embodiments, the assay is an enzymatic assay, and the number ofgroups of molecular scaffolds formed can conveniently be about 500. Insome embodiments, the assay is a competition assay, e.g., a bindingcompetition assay. Cell-based assays can also be used. As indicatedabove, compounds can be used that have low, very low, or extremely lowactivity in a biochemical or cell-based assay.

The modification of a molecular scaffold can be the addition,subtraction, or substitution of a chemical group. The modification maydesirably cause the scaffold to be actively transported to or intoparticular cells and/or a particular organ. In various embodiments, themodification of the compound includes the addition or subtraction of achemical atom, substituent or group, such as, for example, a hydrogen,alkyl, alkoxy, phenoxy, alkenyl, alkynyl, phenylalkyl, hydroxyalkyl,haloalkyl, aryl, arylalkyl, alkyloxy, alkylthio, alkenylthio, phenyl,phenylalkyl, phenylalkylthio, hydroxyalkyl-thio, alkylthiocarbbamylthio,cyclohexyl, pyridyl, piperidinyl, alkylamino, amino, nitro, mercapto,cyano, hydroxyl, a halogen atom, halomethyl, an oxygen atom (e.g.,forming a ketone, ether or N-oxide), and a sulphur atom (e.g., forming athiol, thione, sulfonamide or di-alkylsulfoxide (sulfone)).

In certain embodiments, the information provided by performing X-raycrystallography on the co-crystals is provided to a computer program,wherein the computer program provides a measure of the interactionbetween the molecular scaffold and the protein and a prediction ofchanges in the interaction between the molecular scaffold and theprotein that result from specific modifications to the molecularscaffold, and the molecular scaffold is chemically modified based on theprediction of the biochemical result. The computer program can providethe prediction based on a virtual assay such as, for example, virtualdocking of the compound to the protein, shape-based matching, moleculardynamics simulations, free energy perturbation studies, and similarityto a three-dimensional pharmacophore. A variety of such programs arewell-known in the art.

Chemical modification of a chemically tractable structure can result, orbe selected to provide one or more physical changes, e.g., to result, ina ligand that fills a void volume in the protein-ligand complex, or inan attractive polar interaction being produced in the protein-ligandcomplex. The modification can also result in a sub-structure of theligand being present in a binding pocket of the protein binding sitewhen the protein-ligand complex is formed. After common chemicalstructures of the compounds that bind are identified, the compounds canbe grouped based on having a common chemical sub-structure and arepresentative compound from each group (or a plurality of groups) canbe selected for co-crystallization with the protein and performance ofthe X-ray crystallography. The X-ray crystallography is preferablyperformed on the co-crystals under at least 20, 30, 40, or 50 distinctenvironmental conditions, or more preferably under about 96 distinctenvironmental conditions. The X-ray crystallography and the modificationof a chemically tractable structure of the compound can each beperformed a plurality of times, e.g., 2, 3, 4, or more rounds ofcrystallization and modification.

Also in certain embodiments, one or more molecular scaffolds areselected to have binding to a plurality of members of the PPAR family.

The method can also include the identification of conserved residues ina binding site(s) of a PPAR protein that interact with a molecularscaffold, ligand or other binding compound. Conserved residues can, forexample, be identified by sequence alignment of different members of thePPAR family, and identifying binding site residues that are the same orat least similar between multiple member of the family. Interactingresidues can be characterized as those within a selected distance fromthe binding compound(s), e.g., 3, 3.5, 4, 4.5, or 5 angstroms.

In a related aspect, the invention provides a method of designing aligand that binds to at least one PPAR that is a member of the PPARfamily, by identifying as molecular scaffolds one or more compounds thatbind to binding sites of a plurality of members of the PPAR family,determining the orientation of one or more molecular scaffolds at thebinding site of a PPAR(s) to identify chemically tractable structures ofthe scaffold(s) that, when modified, alter the binding affinity orbinding specificity between the scaffold(s) and the PPAR(s), andsynthesizing a ligand wherein one or more of the chemically tractablestructures of the molecular scaffold(s) is modified to provide a ligandthat binds to the PPAR with altered binding affinity or bindingspecificity.

Particular embodiments include those described for the preceding aspect.

The invention also provides a method to identify properties that alikely binding compound will possess, thereby allowing, for example,more efficient selection of compounds for structure activityrelationship determinations and/or for selection for screening. Thus,another aspect concerns a method for identifying binding characteristicsof a ligand of a PPAR protein, by identifying at least one conservedinteracting residue in the PPAR that interacts with at least two bindingmolecules; and identifying at least one common interaction property ofthose binding molecules with the conserved residue(s). The interactionproperty and location with respect to the structure of the bindingcompound defines the binding characteristic.

In various embodiments, the identification of conserved interactingresidues involves comparing (e.g., by sequence alignment) a plurality ofamino acid sequences in the PPAR family and identifying binding siteresidues conserved in that family; identification of binding siteresidues by determining a co-crystal structure; identifying interactingresidues (preferably conserved residues) within a selected distance ofthe binding compounds, e.g., 3, 3.5, 4, 4.5, or 5 angstroms; theinteraction property involves hydrophobic interaction, charge-chargeinteraction, hydrogen bonding, charge-polar interaction, polar-polarinteraction, or combinations thereof.

Another related aspect concerns a method for developing ligands for aPPAR using a set of scaffolds. The method involves selecting a PPAR orplurality of PPARs, selecting a molecular scaffold, or a compound from ascaffold group, from a set of at least 3 scaffolds or scaffold groupswhere each of the scaffolds or compounds from each scaffold group areknown to bind to the target. In particular embodiments, the set ofscaffolds or scaffold groups is at least 4, 5, 6, 7, 8, or even morescaffolds or scaffold groups.

Another aspect concerns a method for identifying structurally andenergetically allowed sites on a binding compound for attachment of anadditional component(s) by analyzing the orientation of the bindingcompound(s) in a PPAR binding site (e.g., by analyzing co-crystalstructures), thereby identifying accessible sites on the compound forattachment of the separate component. In particular embodiments, thebinding compound is a compound of Formula I.

In various embodiments, the method involves calculating the change inbinding energy on attachment of the separate component at one or more ofthe accessible sites; the orientation is determined byco-crystallography; the separate component includes a linker, a labelsuch as a fluorophore, a solid phase material such as a gel, bead,plate, chip, or well.

In a related aspect, the invention provides a method for attaching aPPAR binding compound to an attachment component(s), by identifyingenergetically allowed sites for attachment of such an attachmentcomponent on a binding compound (e.g., as described for the precedingaspect), and attaching the compound or derivative thereof to theattachment component(s) at the energetically allowed site(s). Inparticular embodiments, the binding compound is a compound of Formula I.

In various embodiments, the attachment component is a linker (which canbe a traceless linker) for attachment to a solid phase medium, and themethod also involves attaching the compound or derivative to a solidphase medium through the linker attached at the energetically allowedsite; the binding compound or derivative thereof is synthesized on alinker attached to the solid phase medium; a plurality of compounds orderivatives are synthesized in combinatorial synthesis; the attachmentof the compound(s) to the solid phase medium provides an affinity medium

A related aspect concerns a method for making an affinity matrix for aPPAR, where the method involves identifying energetically allowed siteson a PPAR binding compound for attachment to a solid phase matrix; andattaching the PPAR binding compound to the solid phase matrix throughthe energetically allowed site. In particular embodiments, the bindingcompound is a compound of Formula I.

Various embodiments are as described for attachment of a separatecomponent above; identifying energetically allowed sites for attachmentto a solid phase matrix is performed for at least 5, 10, 20, 30, 50, 80,or 100 different compounds; identifying energetically allowed sites isperformed for molecular scaffolds or other PPAR binding compounds havingdifferent core ring structures.

As used herein the term “PPAR” refers to a peroxisomeproliferator-activated receptor as recognized in the art. As indicatedabove, the PPAR family includes PPARα (also referred to as PPARa orPPARalpha), PPARδ (also referred to as PPARd or PPARdelta), and PPARγ(also referred to as PPARg or PPARgamma). The individual PPARs can beidentified by their sequences, where exemplary reference sequenceaccession numbers are: NM_(—)005036 (cDNA sequence for hPPARa),NP_(—)005027 (protein sequence for hPPARa), NM_(—)015869 (cDNA sequencefor hPPARg isoform 2), NP_(—)056953 (protein sequence for hPPARg isoform2), NM_(—)006238 (cDNA sequence for hPPARd), and NP_(—)006229 (proteinsequence for hPPARd). One of ordinary skill in the art will recognizethat sequence differences will exist due to allelic variation, and willalso recognize that other animals, particularly other mammals havecorresponding PPARs, which have been identified or can be readilyidentified using sequence alignment and confirmation of activity, canalso be used. One of ordinary skill in the art will also recognize thatmodifications can be introduced in a PPAR sequence without destroyingPPAR activity. Such modified PPARs can also be used in the presentinvention, e.g., if the modifications do not alter the binding siteconformation to the extent that the modified PPAR lacks substantiallynormal ligand binding.

As used herein in connection with the design or development of ligands,the term “bind” and “binding” and like terms refer to a non-convalentenergetically favorable association between the specified molecules(i.e., the bound state has a lower free energy than the separated state,which can be measured calorimetrically). For binding to a target, thebinding is at least selective, that is, the compound bindspreferentially to a particular target or to members of a target familyat a binding site, as compared to non-specific binding to unrelatedproteins not having a similar binding site. For example, BSA is oftenused for evaluating or controlling for non-specific binding. Inaddition, for an association to be regarded as binding, the decrease infree energy going from a separated state to the bound state must besufficient so that the association is detectable in an biochemical assaysuitable for the molecules involved.

By “assaying” is meant the creation of experimental conditions and thegathering of data regarding a particular result of the experimentalconditions. For example, enzymes can be assayed based on their abilityto act upon a detectable substrate. Likewise, for example, a compound orligand can be assayed based on its ability to bind to a particulartarget molecule or molecules and/or to modulate an activity of a targetmolecule.

By “background signal” in reference to a binding assay is meant thesignal that is recorded under standard conditions for the particularassay in the absence of a test compound, molecular scaffold, or ligandthat binds to the target molecule. Persons of ordinary skill in the artwill realize that accepted methods exist and are widely available fordetermining background signal.

When a decision is described as “based on” particular criteria, it ismeant that the criteria selected are parameters of the decision andguide its outcome. A substantial change in the parameters is likely toresult in a change in the decision.

By “binding site” is meant an area of a target molecule to which aligand can bind non-covalently. Binding sites embody particular shapesand often contain multiple binding pockets present within the bindingsite. The particular shapes are often conserved within a class ofmolecules, such as a molecular family. Binding sites within a class alsocan contain conserved structures such as, for example, chemicalmoieties, the presence of a binding pocket, and/or an electrostaticcharge at the binding site or some portion of the binding site, all ofwhich can influence the shape of the binding site.

By “binding pocket” is meant a specific volume within a binding site. Abinding pocket is a particular space within a binding site at leastpartially bounded by target molecule atoms. Thus a binding pocket is aparticular shape, indentation, or cavity in the binding site. Bindingpockets can contain particular chemical groups or structures that areimportant in the non-covalent binding of another molecule such as, forexample, groups that contribute to ionic, hydrogen bonding, van derWaals, or hydrophobic interactions between the molecules.

By “chemical structure” or “chemical substructure” is meant anydefinable atom or group of atoms that constitute a part of a molecule.Normally, chemical substructures of a scaffold or ligand can have a rolein binding of the scaffold or ligand to a target molecule, or caninfluence the three-dimensional shape, electrostatic charge, and/orconformational properties of the scaffold or ligand.

By “orientation”, in reference to a binding compound bound to a targetmolecule is meant the spatial relationship of the binding compound andat least some of its constituent atoms to the binding pocket and/oratoms of the target molecule at least partially defining the bindingpocket.

In the context of target molecules in the present invention, the term“crystal” refers to an ordered complex of target molecule, such that thecomplex produces an X-ray diffraction pattern when placed in an X-raybeam. Thus, a “crystal” is distinguished from a disordered or partiallyordered complex or aggregate of molecules that do not produce such adiffraction pattern. Preferably a crystal is of sufficient order andsize to be useful for X-ray crystallography. A crystal may be formedonly of target molecule (with solvent and ions) or may be a co-crystalof more than one molecule, for example, as a co-crystal of targetmolecule and binding compound, and/or of a complex of proteins (such asa holoenzyme).

In the context of this invention, unless otherwise specified, by“co-crystals” is meant an ordered complex of the compound, molecularscaffold, or ligand bound non-covalently to the target molecule thatproduces a diffraction pattern when placed in an X-ray beam. Preferablythe co-crystal is in a form appropriate for analysis by X-ray or proteincrystallography. In preferred embodiments the target molecule-ligandcomplex can be a protein-ligand complex.

By “clog P” is meant the calculated log P of a compound, “P” referringto the partition coefficient of the compound between a lipophilic and anaqueous phase, usually between octanol and water.

By “chemically tractable structures” is meant chemical structures,sub-structures, or sites on a molecule that can be covalently modifiedto produce a ligand with a more desirable property. The desirableproperty will depend on the needs of the particular situation. Theproperty can be, for example, that the ligand binds with greateraffinity to a target molecule, binds with more specificity, or binds toa larger or smaller number of target molecules in a molecular family, orother desirable properties as needs require.

By “designing a ligand,” “preparing a ligand,” “discovering a ligand,”and like phrases is meant the process of considering relevant data(especially, but not limited to, any individual or combination ofbinding data, X-ray co-crystallography data, molecular weight, clogP,and the number of hydrogen bond donors and acceptors) and makingdecisions about advantages that can be achieved with resort to specificstructural modifications to a molecule, and implementing thosedecisions. This process of gathering data and making decisions aboutstructural modifications that can be advantageous, implementing thosedecisions, and determining the result can be repeated as many times asnecessary to obtain a ligand with desired properties.

By “docking” is meant the process of attempting to fit athree-dimensional configuration of a binding pair member into athree-dimensional configuration of the binding site or binding pocket ofthe partner binding pair member, which can be a protein, and determiningthe extent to which a fit is obtained. The extent to which a fit isobtained can depend on the amount of void volume in the resultingbinding pair complex (or target molecule-ligand complex). Theconfiguration can be physical or a representative configuration of thebinding pair member, e.g., an in silico representation or other model.

In the context of development of modulators using molecular scaffolds,by “ligand” is meant a molecular scaffold that has been chemicallymodified at one or more chemically tractable structures to bind to thetarget molecule with altered or changed binding affinity or bindingspecificity relative to the molecular scaffold. The ligand can bind witha greater specificity or affinity for a member of the molecular familyrelative to the molecular scaffold. A ligand binds non-covalently to atarget molecule, which can preferably be a protein or enzyme.

By binding with “low affinity” is meant binding to the target moleculewith a dissociation constant (k_(d)) of greater than 1 μM under standardconditions. In particular cases, low affinity binding is in a range of 1μM-10 mM, 1 μM-1 mM, 1 μM-500 μM, 1 μM-200 μM, 1 μM-100 μM. By bindingwith “very low affinity” is meant binding with a k_(d) of above about100 μM under standard conditions, e.g., in a range of 100 μM-1 mM, 100μM-500 μM, 100 μM-200 μM. By binding with “extremely low affinity” ismeant binding at a k_(d) of above about 1 mM under standard conditions.By “moderate affinity” is meant binding with a k_(d) of from about 200nM to about 1 μM under standard conditions. By “moderately highaffinity” is meant binding at a k_(d) of from about 1 nM to about 200nM. By binding at “high affinity” is meant binding at a k_(d) of belowabout 1 nM under standard conditions. For example, low affinity bindingcan occur because of a poorer fit into the binding site of the targetmolecule or because of a smaller number of non-covalent bonds, or weakercovalent bonds present to cause binding of the scaffold or ligand to thebinding site of the target molecule relative to instances where higheraffinity binding occurs. The standard conditions for binding are at pH7.2 at 37° C. for one hour. For example, 100 μl/well can be used inHEPES 50 mM buffer at pH 7.2, NaCl 15 mM, ATP 2 μM, and bovine serumalbumin 1 ug/well, 37° C. for one hour.

Binding compounds can also be characterized by their effect on theactivity of the target molecule. Thus, a “low activity” compound has aninhibitory concentration (IC₅₀) (for inhibitors or antagonists) oreffective concentration (EC₅₀) (applicable to agonists) of greater than1 μM under standard conditions. By “very low activity” is meant an IC₅₀or EC₅₀ of above 100 μM under standard conditions. By “extremely lowactivity” is meant an IC₅₀ or EC₅₀ of above 1 mM under standardconditions. By “moderate activity” is meant an IC₅₀ or EC₅₀ of 200 nM to1 μM under standard conditions. By “moderately high activity” is meantan IC₅₀ or EC₅₀ of 1 nM to 200 nM. By “high activity” is meant an IC₅₀or EC₅₀ of below 1 nM under standard conditions. The IC₅₀ (or EC₅₀) isdefined as the concentration of compound at which 50% of the activity ofthe target molecule (e.g., enzyme or other protein) activity beingmeasured is lost (or gained) relative to activity when no compound ispresent. Activity can be measured using methods known to those ofordinary skill in the art, e.g., by measuring any detectable product orsignal produced by occurrence of an enzymatic reaction, or otheractivity by a protein being measured. For PPAR agonists, activities canbe determined as described in the Examples, or using other such assaymethods known in the art.

By “molecular scaffold” or “scaffold” is meant a small target bindingmolecule to which one or more additional chemical moieties can becovalently attached, modified, or eliminated to form a plurality ofmolecules with common structural elements. The moieties can include, butare not limited to, a halogen atom, a hydroxyl group, a methyl group, anitro group, a carboxyl group, or any other type of molecular groupincluding, but not limited to, those recited in this application.Molecular scaffolds bind to at least one target molecule with low orvery low affinity and/or bind to a plurality of molecules in a targetfamily (e.g., protein family), and the target molecule is preferably anenzyme, receptor, or other protein. Preferred characteristics of ascaffold include molecular weight of less than about 350 daltons;binding at a target molecule binding site such that one or moresubstituents on the scaffold are situated in binding pockets in thetarget molecule binding site; having chemically tractable structuresthat can be chemically modified, particularly by synthetic reactions, sothat a combinatorial library can be easily constructed; having chemicalpositions where moieties can be attached that do not interfere withbinding of the scaffold to a protein binding site, such that thescaffold or library members can be modified to form ligands, to achieveadditional desirable characteristics, e.g., enabling the ligand to beactively transported into cells and/or to specific organs, or enablingthe ligand to be attached to a chromatography column for additionalanalysis. Thus, a molecular scaffold is a small, identified targetbinding molecule prior to modification to improve binding affinityand/or specificity, or other pharmacalogic properties.

The term “scaffold core” refers to the core structure of a molecularscaffold onto which various substituents can be attached. Thus, for anumber of scaffold molecules of a particular chemical class, thescaffold core is common to all the scaffold molecules. In many cases,the scaffold core will consist of or include one or more ringstructures.

The term “scaffold group” refers to a set of compounds that share ascaffold core and thus can all be regarded as derivatives of onescaffold molecule.

By “molecular family” is meant groups of molecules classed togetherbased on structural and/or functional similarities. Examples ofmolecular families include proteins, enzymes, polypeptides, receptormolecules, oligosaccharides, nucleic acids, DNA, RNA, etc. Thus, forexample, a protein family is a molecular family. Molecules can also beclassed together into a family based on, for example, homology. Theperson of ordinary skill in the art will realize many other moleculesthat can be classified as members of a molecular family based onsimilarities in chemical structure or biological function.

By “protein-ligand complex” or “co-complex” is meant a protein andligand bound non-covalently together.

By “protein” is meant a polymer of amino acids. The amino acids can benaturally or non-naturally occurring. Proteins can also containadaptations, such as being glycosylated, phosphorylated, or other commonmodifications.

By “protein family” is meant a classification of proteins based onstructural and/or functional similarities. For example, kinases,phosphatases, proteases, and similar groupings of proteins are proteinfamilies. Proteins can be grouped into a protein family based on havingone or more protein folds in common, a substantial similarity in shapeamong folds of the proteins, homology, or based on having a commonfunction. In many cases, smaller families will be specified, e.g., thePPAR family.

“Protein folds” are 3-dimensional shapes exhibited by the protein anddefined by the existence, number, and location in the protein of alphahelices, beta-sheets, and loops,

i.e., the basic secondary structures of protein molecules. Folds can be,for example, domains or partial domains of a particular protein.

By “ring structure” is meant a molecule having a chemical ring orsub-structure that is a chemical ring. In most cases, ring strutureswill be carbocyclic or heterocyclic rings. The chemical ring may be, butis not limited to, a phenyl ring, aryl ring, pyrrole ring, imidazole,pyridine, purine, or any ring structure.

By “specific biochemical effect” is meant a therapeutically significantbiochemical change in a biological system causing a detectable result.This specific biochemical effect can be, for example, the inhibition oractivation of an enzyme, the inhibition or activation of a protein thatbinds to a desired target, or similar types of changes in the body'sbiochemistry. The specific biochemical effect can cause alleviation ofsymptoms of a disease or condition or another desirable effect. Thedetectable result can also be detected through an intermediate step.

By “standard conditions” is meant conditions under which an assay isperformed to obtain scientifically meaningful data. Standard conditionsare dependent on the particular assay, and can be generally subjective.Normally the standard conditions of an assay will be those conditionsthat are optimal for obtaining useful data from the particular assay.The standard conditions will generally minimize background signal andmaximize the signal sought to be detected.

By “standard deviation” is meant the square root of the variance. Thevariance is a measure of how spread out a distribution is. It iscomputed as the average squared deviation of each number from its mean.For example, for the numbers 1, 2, and 3, the mean is 2 and the varianceis:

$\sigma^{2} = {\frac{\left( {1 - 2} \right)^{2} + \left( {2 - 2} \right)^{2} + \left( {3 - 2} \right)^{2}}{3} = {0.667.}}$

By a “set” of compounds is meant a collection of compounds. Thecompounds may or may not be structurally related.

In the context of this invention, by “target molecule” is meant amolecule that a compound, molecular scaffold, or ligand is being assayedfor binding to. The target molecule has an activity that binding of themolecular scaffold or ligand to the target molecule will alter orchange. The binding of the compound, scaffold, or ligand to the targetmolecule can preferably cause a specific biochemical effect when itoccurs in a biological system. A “biological system” includes, but isnot limited to, a living system such as a human, animal, plant, orinsect. In most but not all cases, the target molecule will be a proteinor nucleic acid molecule.

By “pharmacophore” is meant a representation of molecular features thatare considered to be responsible for a desired activity, such asinteracting or binding with a receptor. A pharmacophore can include3-dimensional (hydrophobic groups, charged/ionizable groups, hydrogenbond donors/acceptors), 2D (substructures), and 1D (physical orbiological) properties.

As used herein in connection with numerical values, the terms“approximately” and “about” mean±10% of the indicated value.

Additional embodiments will be apparent from the Detailed Descriptionand from the claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As indicated in the Summary above, the present invention concerns theperoxisome proliferator-activated receptors (PPARs), which have beenidentified in humans and other mammals. A group of compounds have beenidentified, corresponding to Formula I, that are active on one or moreof the PPARs, in particular compounds that are active one or more humanPPARs.

The identification of these compound provides compounds that can be usedas agonists on PPARs, as well as for identification or development ofadditional active compounds, for example, compounds within Formula I.

I. Applications of PPAR Agonists

The PPARs have been recognized as suitable targets for a number ofdifferent disease and conditions. Some of those applications aredescribed briefly below. Additional applications are known and thepresent compounds can also be used for those diseases and conditions.

(a) Insulin resistance and diabetes: In connection with insulinresistance and diabetes, PPARγ is necessary and sufficient for thedifferentiation of adipocytes in vitro and in vivo. In adipocytes, PPARγincreases the expression of numerous genes involved in lipid metabolismand lipid uptake. In contrast, PPARγ down-regulates leptin, a secreted,adipocyte-selective protein that has been shown to inhibit feeding andaugment catabolic lipid metabolism. This receptor activity could explainthe increased caloric uptake and storage noted in vivo upon treatmentwith PPARγ agonists. Clinically, TZDs, including troglitazone,rosiglitazone, and pioglitazone, and non-TZDs, including farglitazar,have insulin-sensitizing and antidiabetic activity. (Berger et al.,2002, Diabetes Tech. And Ther. 4:163-174.)

PPARγ has been associated with several genes that affect insulin action.TNFα, a proinflammatory cytokine that is expressed by adipocytes, hasbeen associated with insulin resistance. PPARγ agonists inhibitedexpression of TNFα in adipose tissue of obese rodents, and ablated theactions of TNFα in adipocytes in vitro. PPARγ agonists were shown toinhibit expression of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD-1),the enzyme that converts cortisone to the glucocorticoid agonistcortisol, in adipocytes and adipose tissue of type 2 diabetes mousemodels. This is noteworthy since hypercortico-steroidism exacerbatesinsulin resistance. Adipocyte Complement-Related Protein of 30 kDa(Acrp30 or adiponectin) is a secreted adipocyte-specific protein thatdecreases glucose, triglycerides, and free fatty acids. In comparison tonormal human subjects, patients with type 2 diabetes have reduced plasmalevels of Acrp30. Treatment of diabetic mice and nondiabetic humansubjects with PPARγ agonists increased plasma levels of Acrp30.Induction of Acrp30 by PPARγ agonists might therefore also play a keyrole in the insulin-sensitizing mechanism of PPARγ agonists in diabetes.(Berger et al., 2002, Diabetes Tech. And Ther. 4:163-174.)

PPARγ is expressed predominantly in adipose tissue. Thus, it is believedthat the net in vivo efficacy of PPARγ agonists involves direct actionson adipose cells with secondary effects in key insulin responsivetissues such as skeletal muscle and liver. This is supported by the lackof glucose-lowering efficacy of rosiglitazone in a mouse model of severeinsulin resistance where white adipose tissue was essentially absent.Furthermore, in vivo treatment of insulin resistant rats produces acute(<24 h) normalization of adipose tissue insulin action whereasinsulin-mediated glucose uptake in muscle was not improved until severaldays after the initiation of therapy. This is consistent with the factthat PPARγ agonists can produce an increase in adipose tissue insulinaction after direct in vitro incubation, whereas no such effect could bedemonstrated using isolated in vitro incubated skeletal muscles. Thebeneficial metabolic effects of PPARγ agonists on muscle and liver maybe mediated by their ability to (a) enhance insulin-mediated adiposetissue uptake, storage (and potentially catabolism) of free fatty acids;(b) induce the production of adipose-derived factors with potentialinsulin sensitizing activity (e.g., Acrp30); and/or (c) suppress thecirculating levels and/or actions of insulin resistance-causingadipose-derived factors such as TNFα or resistin. (Berger et al., 2002,Diabetes Tech. And Ther. 4:163-174.)

(b) Dyslipidemia and atherosclerosis: In connection with dyslipidemiaand atherosclerosis, PPARα has been shown to play a critical role in theregulation of cellular uptake, activation, and α-oxidation of fattyacids. Activation of PPARα induces expression of fatty acid transportproteins and enzymes in the peroxisomal β-oxidation pathway. Severalmitochondrial enzymes involved in the energy-harvesting catabolism offatty acids are robustly upregulated by PPARα agonists. Peroxisomeproliferators also activate expression of the CYP4As, a subclass ofcytochrome P450 enzymes that catalyze the ω-hydroxylation of fattyacids, a pathway that is particularly active in the fasted and diabeticstates. In sum, it is clear that PPARα is an important lipid sensor andregulator of cellular energy-harvesting metabolism. (Berger et al.,2002, Diabetes Tech. And Ther. 4:163-174.)

Atherosclerosis is a very prevalent disease in Westernized societies. Inaddition to a strong association with elevated LDL cholesterol,“dyslipidemia” characterized by elevated triglyceride-rich particles andlow levels of HDL cholesterol is commonly associated with other aspectsof a metabolic syndrome that includes obesity, insulin resistance, type2 diabetes, and an increased risk of coronary artery disease. Thus, in8,500 men with known coronary artery disease, 38% were found to have lowHDL (<35 mg/dL) and 33% had elevated triglycerides (>200 mg/dL). In suchpatients, treatment with fibrates resulted in substantial triglyceridelowering and modest HDL-raising efficacy. More importantly, a recentlarge prospective trial showed that treatment with gemfibrozil produceda 22% reduction in cardiovascular events or death. Thus PPARα agonistscan effectively improve cardiovascular risk factors and have a netbenefit to improve cardiovascular outcomes. In fact, fenofibrate wasrecently approved in the United States for treatment of type IIA and IIBhyper-lipidemia. Mechanisms by which PPARα activation cause triglyceridelowering are likely to include the effects of agonists to suppresshepatic apo-CIII gene expression while also stimulating lipoproteinlipase gene expression. Dual PPARγ/α agonists, including KRP-297 and DRF2725, possess potent lipid-altering efficacy in addition toantihyperglycemic activity in animal models of diabetes and lipiddisorders.

The presence of PPARα and/or PPARγ expression in vascular cell types,including macrophages, endothelial cells, and vascular smooth musclecells, suggests that direct vascular effects might contribute topotential antiatherosclerosis efficacy. PPARα and PPARα activation havebeen shown to inhibit cytokine-induced vascular cell adhesion and tosuppress monocyte-macrophage migration. Several additional studies havealso shown that PPARγ-selective compounds have the capacity to reducearterial lesion size and attenuate monocyte-macrophage homing toarterial lesions in animal models of atherosclerosis. In addition, tworecent studies have suggested that either PPARα or PPARγ activation inmacrophages can induce the expression of a cholesterol efflux “pump”protein.

It has been found that relatively selective PPARγ agonists produceminimal, if any, glucose- or triglyceride-lowering activity in murinemodels of type 2 diabetes in comparison with efficacious PPARγ or PPARαagonists. Subsequently, a modest increase in HDL-cholesterol levels wasdetected with PPARδ agonists in db/db mice. Recently, Oliver et al.reported that a potent, selective PPARδ agonist could induce asubstantial increase in HDL-cholesterol levels while reducingtriglyceride levels and insulin resistance in obese rhesus monkeys.

Thus, via multifactorial mechanisms that include improvements incirculating lipids, systemic and local antiinflammatory effects, and,inhibition of vascular cell proliferation, PPARα, PPARγ, and PPARδagonists can be used in the treatment or prevention of atherosclerosis.(Berger et al., 2002, Diabetes Tech. And Ther. 4:163-174.)

(c) Inflammation: Monocytes and macrophages are known to play animportant part in the inflammatory process through the release ofinflammatory cytokines and the production of nitric oxide by induciblenitric oxide synthase. Rosiglitazone has been shown to induce apoptosisof macrophages at concentrations that paralleled its affinity for PPARγ.This ligand has also been show to block inflammatory cytokine synthesisin colonic cell lines. This latter observation suggests a mechanisticexplanation for the observed anti-inflammatory actions of TZDs in rodentmodels of colitis.

Anti-inflammatory actions have been described for PPARα ligands that canbe important in the maintenance of vascular health. Treatment ofcytokine-activated human macrophages with PPARα agonists inducedapoptosis of the cells. It was reported that PPARα agonists inhibitedactivation of aortic smooth muscle cells in response to inflammatorystimuli. (Staels et al., 1998, Nature 393:790-793.) In hyperlipidemicpatients, fenofibrate treatment decreased the plasma concentrations ofthe inflammatory cytokine interleukin-6

(d) Hypertension: Hypertension is a complex disorder of thecardiovascular system that has been shown to be associated with insulinresistance. Type 2 diabetes patients demonstrate a 1.5-2-fold increasein hypertension in comparison with the general population. Troglitazone,rosiglitazone, and pioglitazone therapy have been shown to decreaseblood pressure in diabetic patients as well as troglitazone therapy inobese, insulin-resistant subjects. Since such reductions in bloodpressure were shown to correlate with decreases in insulin levels, theycan be mediated by an improvement in insulin sensitivity. However, sinceTZDs also lowered blood pressure in one-kidney one-clip Sprague Dawleyrats, which are not insulin resistant, it was proposed that thehypotensive action of PPARγ agonists is not exerted solely through theirability to improve insulin sensitivity. Other mechanisms that have beeninvoked to explain the antihypertensive effects of PPARγ agonistsinclude their ability to (a) downregulate expression of peptides thatcontrol vascular tone such as PAI-I, endothelin, and type-c natriureticpeptide C or (b) alter calcium concentrations and the calciumsensitivity of vascular cells. (Berger et al., 2002, Diabetes Tech. AndTher. 4:163-174.)

In accordance with the description above, isoforms of the PPAR family ofnuclear receptors are clearly involved in the systemic regulation oflipid metabolism and serve as “sensors” for fatty acids, prostanoidmetabolites, eicosanoids and related molecules. These receptors functionto regulate a broad array of genes in a coordinate fashion. Importantbiochemical pathways that regulate insulin action, lipid oxidation,lipid synthesis, adipocyte differentiation, peroxisome function, cellapoptosis, and inflammation can be modulated through the individual PPARisoforms. Strong therapeutic effects of PPARα and PPARγ agonists tofavorably influence systemic lipid levels, glucose homeostasis, andatherosclerosis risk (in the case of PPARα activation in humans) haverecently been discovered. PPARα and PPARγ agonists are presently usedclinically to favorably alter systemic lipid levels and glucosehomeostasis, respectively. Recent observations made using PPARS ligandssuggest that this isoform is also an important therapeutic target fordyslipidemia and insulin resistance, as well.

Thus, PPAR agonists, such as those described herein, can be used in theprophylaxix and/or therapeutic treatment of a variety of differentdisease and conditions, such as obesity, overweight condition,hyperlipidemia, dyslipidemia including associated diabetic dyslipidemiaand mixed dyslipidemia, hypoalphalipoproteinemia, Syndrome X, Type IIdiabetes mellitus, Type I diabetes, hyperinsulinemia, impaired glucosetolerance, insulin resistance, a diabetic complication (e.g.,neuropathy, nephropathy, retinopathy or cataracts), hypertension,coronary heart disease, heart failure, hypercholesterolemia,inflammation, thrombosis, congestive heart failure, cardiovasculardisease (including atherosclerosis, arteriosclerosis, andhypertriglyceridemia), epithelial hyperproliferative diseases (such aseczema and psoriasis), and conditions associated with the lung and gutand regulation of appetite and food intake in subjects suffering fromdisorders such as obesity, anorexia bulimia and anorexia nervosa.

(e) Cancer: PPAR modulation has also been correlated with cancertreatment. (Burstein et al.; Breast Cancer Res. Treat. 2003 79(3):391-7;Alderd et al.; Oncogene, 2003, 22(22):3412-6).

(f) Weight Control: Administration of PPARα agonists can induce satiety,and thus are useful in weight loss or maintenance. Such PPARα agonistscan act preferentially on PPARα, or can also act on another PPAR, or canbe PPAR pan-agonists. Thus, the satiety inducing effect of PPARαagonists can be used for weight control or loss.

II. PPAR Active Compounds

As indicated in the Summary and in connection with applicable diseasesand conditions, a number of different PPAR agonists have beenidentified. In addition, the present invention provides PPAR agonistcompounds described by Formula I as provided in the Summary above.Included within Formula I are sub-groups of compounds, for example,sub-groups shown by the structures Ia, Ib, Ic, Id, X, and XIV as shownin the synthetic schemes below. Included within such compounds ofFormula I, are exemplary compounds provided in Table 1 below. Additionalcompounds within Formula I can also be prepared and tested to confirmactivity using conventional methods and the guidance provided herein.

III. Development of PPAR Active Compounds

A. Modulator identification and design

A large number of different methods can be used to identify modulatorsand to design improved modulators. Some useful methods involvestructure-based design.

Structure-based modulator design and identification methods are powerfultechniques that can involve searches of computer databases containing awide variety of potential modulators and chemical functional groups. Thecomputerized design and identification of modulators is useful as thecomputer databases contain more compounds than the chemical libraries,often by an order of magnitude. For reviews of structure-based drugdesign and identification (see Kuntz et al. (1994), Acc. Chem. Res.27:117; Guida (1994) Current Opinion in Struc. Biol. 4: 777; Colman(1994) Current Opinion in Struc. Biol. 4: 868).

The three dimensional structure of a polypeptide defined by structuralcoordinates can be utilized by these design methods, for example, thestructural coordinates of a PPAR. In addition, the three dimensionalstructures of PPARs determined by the homology, molecular replacement,and NMR techniques can also be applied to modulator design andidentification methods.

For identifying modulators, structural information for a PPAR, inparticular, structural information for the active site of the PPAR canbe used. However, it may be advantageous to utilize structuralinformation from one or more co-crystals of the PPAR with one or morebinding compounds. It can also be advantageous if the binding compoundhas a structural core in common with test compounds.

Such modulator identification and design can, for example, be used toidentify and/or develop additional active compounds within Formula I (asub-group thereof).

1. Design by Searching Molecular Data Bases

One method of rational design searches for modulators by docking thecomputer representations of compounds from a database of molecules.Publicly available databases include, for example:

a) ACD from Molecular Designs Limited

b) NCI from National Cancer Institute

c) CCDC from Cambridge Crystallographic Data Center

d) CAST from Chemical Abstract Service

e) Derwent from Derwent Information Limited

f) Maybridge from Maybridge Chemical Company LTD

g) Aldrich from Aldrich Chemical Company

h) Directory of Natural Products from Chapman & Hall

One such data base (ACD distributed by Molecular Designs LimitedInformation Systems) contains compounds that are synthetically derivedor are natural products. Methods available to those skilled in the artcan convert a data set represented in two dimensions to one representedin three dimensions. These methods are can be carried out using suchcomputer programs as CONCORD from Tripos Associates or DE-Converter fromMolecular Simulations Limited.

Multiple methods of structure-based modulator design are known to thosein the art. (Kuntz et al., (1982), J. Mol. Biol. 162: 269; Kuntz et aZ.,(1994), Acc. Chem. Res. 27: 117; Meng et al., (1992), J. Compt. Chem.13: 505; Bohm, (1994), J. Comp. Aided Molec. Design 8: 623.)

A computer program widely utilized by those skilled in the art ofrational modulator design is DOCK from the University of California inSan Francisco. The general methods utilized by this computer program andprograms like it are described in three applications below. Moredetailed information regarding some of these techniques can be found inthe Accelerys User Guide, 1995. A typical computer program used for thispurpose can perform a processes comprising the following steps orfunctions:

-   -   (a) remove the existing compound from the protein;    -   (b) dock the structure of another compound into the active-site        using the computer program (such as DOCK) or by interactively        moving the compound into the active-site;    -   (c) characterize the space between the compound and the        active-site atoms;    -   (d) search libraries for molecular fragments which (i) can fit        into the empty space between the compound and the active-site,        and (ii) can be linked to the compound; and    -   (e) link the fragments found above to the compound and evaluate        the new modified compound.

Part (c) refers to characterizing the geometry and the complementaryinteractions formed between the atoms of the active site and thecompounds. A favorable geometric fit is attained when a significantsurface area is shared between the compound and active-site atomswithout forming unfavorable steric interactions. One skilled in the artwould note that the method can be performed by skipping parts (d) and(e) and screening a database of many compounds.

Structure-based design and identification of modulators of PPAR functioncan be used in conjunction with assay screening. As large computerdatabases of compounds (around 10,000 compounds) can be searched in amatter of hours or even less, the computer-based method can narrow thecompounds tested as potential modulators of PPAR function in biochemicalor cellular assays.

The above descriptions of structure-based modulator design are not allencompassing and other methods are reported in the literature and can beused, e.g.:

-   -   (1) CAVEAT: Bartlett et al., (1989), in Chemical and Biological        Problems in Molecular Recognition, Roberts, S. M.; Ley, S. V.;        Campbell, M. M. eds.; Royal Society of Chemistry: Cambridge, pp.        182-196.    -   (2) FLOG: Miller et al., (1994), J. Comp. Aided Molec. Design        8:153.    -   (3) PRO Modulator: Clark et al., (1995), J. Comp. Aided Molec.        Design 9:13.    -   (4) MCSS: Miranker and Karplus, (1991), Proteins: Structure,        Function, and Genetics 11:29.    -   (5) AUTODOCK: Goodsell and Olson, (1990), Proteins: Structure,        Function, and Genetics 8:195.    -   (6) GRID: Goodford, (1985), J. Med. Chem. 28:849.

2. Design by Modifying Compounds in Complex with a PPAR

Another way of identifying compounds as potential modulators is tomodify an existing modulator in the polypeptide active site. Forexample, the computer representation of modulators can be modifiedwithin the computer representation of a PPAR active site. Detailedinstructions for this technique can be found, for example, in theAccelerys User Manual, 1995 in LUDI. The computer representation of themodulator is typically modified by the deletion of a chemical group orgroups or by the addition of a chemical group or groups.

Upon each modification to the compound, the atoms of the modifiedcompound and active site can be shifted in conformation and the distancebetween the modulator and the active-site atoms may be scored along withany complementary interactions formed between the two molecules. Scoringcan be complete when a favorable geometric fit and favorablecomplementary interactions are attained. Compounds that have favorablescores are potential modulators.

3. Design by Modifying the Structure of Compounds that Bind a PPAR

A third method of structure-based modulator design is to screencompounds designed by a modulator building or modulator searchingcomputer program. Examples of these types of programs can be found inthe Molecular Simulations Package, Catalyst. Descriptions for using thisprogram are documented in the Molecular Simulations User Guide (1995).Other computer programs used in this application are ISIS/HOST,ISIS/BASE, ISIS/DRAW) from Molecular Designs Limited and UNITY fromTripos Associates.

These programs can be operated on the structure of a compound that hasbeen removed from the active site of the three dimensional structure ofa compound-PPAR complex. Operating the program on such a compound ispreferable since it is in a biologically active conformation.

A modulator construction computer program is a computer program that maybe used to replace computer representations of chemical groups in acompound complexed with a PPAR or other biomolecule with groups from acomputer database. A modulator searching computer program is a computerprogram that may be used to search computer representations of compoundsfrom a computer data base that have similar three dimensional structuresand similar chemical groups as compound bound to a particularbiomolecule.

A typical program can operate by using the following general steps:

-   -   (a) map the compounds by chemical features such as by hydrogen        bond donors or acceptors, hydrophobic/lipophilic sites,        positively ionizable sites, or negatively ionizable sites;    -   (b) add geometric constraints to the mapped features; and    -   (c) search databases with the model generated in (b).

Those skilled in the art also recognize that not all of the possiblechemical features of the compound need be present in the model of (b).One can use any subset of the model to generate different models fordata base searches.

B. Identification of Active Compounds Using PPAR Structure and MolecularScaffolds

In addition to the methods described above that are normally appliedbased on screening hits that have a substantial level of activity, theavailability of crystal structures that include ligand binding sites forthe various PPARs provides application of a scaffold method foridentifying and developing additional PPAR active compounds. As anexample, such a scaffold method can be applied using molecular scaffoldswithin Formula I, or having a scaffold core of Formula I, but can alsobe applied to other molecular scaffolds that are identified.

Thus, the present invention also concerns methods for designing ligandsactive on PPARs by using structural information about the ligand bindingsites and identified PPAR binding compounds. While such methods can beimplemented in many ways (e.g., as described above), highly preferablythe process utilizes molecular scaffolds. Such development processes andrelated methods are described generally below, and can, as indicated byapplied to the PPARs, individually and/or in any pair, or as a family.

Molecular scaffolds are low molecular weight molecules that bind withlow or very low affinity to the target and typically have low or verylow activity on that target and/or act broadly across families of targetmolecules. The ability of a scaffold or other compound to act broadlyacross multiple members of a target family is advantageous in developingligands. For example, a scaffold or set of scaffolds can serve asstarting compounds for developing ligands with desired specificity orwith desired cross-activity on a selected subset of members of a targetfamily. Further, identification of a set of scaffolds that each bindwith members of a target family provides an advantageous basis forselecting a starting point for ligand development for a particulartarget or subset of targets. In many cases, the ability of a scaffold tobind to and/or have activity on multiple members of a target family isrelated to active site or binding site homology that exists across thetarget family.

A scaffold active across multiple members of the target family interactswith surfaces or residues of relatively high homology, i.e., binds toconserved regions of the binding pockets. Scaffolds that bind withmultiple members can be modified to provide greater specficity or tohave a particular cross-reactivity, e.g., by exploiting differencesbetween target binding sites to provide specificity, and exploitingsimilarities to design in cross-reactivities. Adding substituents thatprovide attractive interactions with the particular target typicallyincreases the binding affinity, often increasing the activity. Thevarious parts of the ligand development process are described in moredetail in following sections, but the following describes anadvantageous approach for scaffold-based ligand development.

Scaffold-based ligand development (scaffold-based drug discovery) can beimplemented in a variety of ways, but large scale expression of proteinis useful to provide material for crystallization, co-crystallization,and biochemical screening (e.g., binding and activity assays). Forcrystallization, crystallization conditions can be established for apoprotein and a structure determined from those crystals. For screening,preferably a biased library selected for the particular target family isscreening for binding and/or activity on the target. Highly preferably aplurality of members from the target family is screened. Such screening,whether on a single target or on multiple members of a target familyprovides screening hits. Low affinity and/or low activity hits areselected. Such low affinity hits can either identify a scaffoldmolecule, or allow identification of a scaffold molecule by analyzingcommon features between binding molecules. Simpler molecules containingthe common features can then be tested to determine if they retainbinding and/or activity, thereby allowing identification of a scaffoldmolecule.

When multiple members of a particular target family are used forscreening, the overlap in binding and/or activity of compounds canprovide a useful selection for compounds that will be subjected tocrystallization. For example, for 3 target molecules from a targetfamily, if each target has about 200-500 hits in screening of aparticular library, much smaller subsets of those hits will be common toany 2 of the 3 targets, and a still smaller subset will be common to all3 targets, e.g., 100-300. In many cases, compounds in the subset commonto all 3 targets will be selected for co-crystallography, as theyprovide the broadest potential for ligand development.

Once compounds for co-crystallography are selected, conditions forforming co-crystals are determined, allowing determination of co-crystalstructure and the orientation of binding compound in the binding site ofthe target is determined by solving the structure (this can be highlyassisted if an apo protein crystal structure has been determined or ifthe structure of a close homolog is available for use in a homologymodel. Preferably the co-crystals are formed by directco-crystallization rather than by soaking the compound into crystals ofapo protein.

From the co-crystals and knowledge of the structure of the bindingcompounds, additional selection of scaffolds or other binding compoundscan be made by applying selection filters, e.g., for (1) binding mode,(2) multiple sites for substitution, and/or (3) tractable chemistry. Abinding mode filter can, for example, be based on the demonstration of adominant binding mode. That is, a scaffold or compounds of a scaffoldgroup bind with a consistent orientation, preferably a consistentorientation across multiple members of a target family. Filteringscaffolds for multiple sites for substitution provides greater potentialfor developing ligands for specific targets due to the greater capacityfor appropriately modifying the structure of the scaffold. Filtering fortractable chemistry also facilitates preparation of ligands derived froma scaffold because the synthetic paths for making derivative compoundsare available. Carrying out such a process of development providesscaffolds, preferably of divergent structure.

In some cases, it may be impractical or undesirable to work with aparticular target for some or all of the development process. Forexample, a particular target may be difficult to express, by easilydegraded, or be difficult to crystallize. In these cases, a surrogatetarget from the target family can be used. It is desirable to have thesurrogate be as similar as possible to the desired target, thus a familymember that has high homology in the binding site should be used, or thebinding site can be modified to be more similar to that of the desiredtarget, or part of the sequence of the desired target can be inserted inthe family member replacing the corresponding part of the sequence ofthe family member.

Once one or more scaffolds are identified for a target family, thescaffolds can be used to develop multiple products directed at specificmembers of the family, or at specific subsets of family members. Thus,starting from a scaffold that acts on multiple member of the targetfamily, derivative compounds (ligands) can be designed and tested thathave increasing selectivity. In addition, such ligands are typicallydeveloped to have greater activity, and will also typically have greaterbinding affinity. In this process, starting with the broadly actingscaffold, ligands are developed that have improved selectivity andactivity profiles, leading to identification of lead compounds for drugdevelopment, leading to drug candidates, and final drug products.

C. Scaffolds

Typically it is advantageous to select scaffolds (and/or compound setsor libraries for scaffold or binding compound identification) withparticular types of characteristics, e.g., to select compounds that aremore likely to bind to a particular target and/or to select compoundsthat have physical and/or synthetic properties to simplify preparationof derivatives, to be drug-like, and/or to provide convenient sites andchemistry for modification or synthesis.

Useful chemical properties of molecular scaffolds can include one ormore of the following characteristics, but are not limited thereto: anaverage molecular weight below about 350 daltons, or between from about150 to about 350 daltons, or from about 150 to about 300 daltons; havinga clogP below 3; a number of rotatable bonds of less than 4; a number ofhydrogen bond donors and acceptors below 5 or below 4; a Polar SurfaceArea of less than 100 Å².; binding at protein binding sites in anorientation so that chemical substituents from a combinatorial librarythat are attached to the scaffold can be projected into pockets in theprotein binding site; and possessing chemically tractable structures atits substituent attachment points that can be modified, thereby enablingrapid library construction.

The term “Molecular Polar Surface Area (PSA)” refers to the sum ofsurface contributions of polar atoms (usually oxygens, nitrogens andattached hydrogens) in a molecule. The polar surface area has been shownto correlate well with drug transport properties, such as intestinalabsorption, or blood-brain barrier penetration.

Additional useful chemical properties of distinct compounds forinclusion in a combinatorial library include the ability to attachchemical moieties to the compound that will not interfere with bindingof the compound to at least one protein of interest, and that willimpart desirable properties to the library members, for example, causingthe library members to be actively transported to cells and/or organs ofinterest, or the ability to attach to a device such as a chromatographycolumn (e.g., a streptavidin column through a molecule such as biotin)for uses such as tissue and proteomics profiling purposes.

A person of ordinary skill in the art will realize other properties thatcan be desirable for the scaffold or library members to have dependingon the particular requirements of the use, and that compounds with theseproperties can also be sought and identified in like manner. Methods ofselecting compounds for assay are known to those of ordinary skill inthe art, for example, methods and compounds described in U.S. Pat. Nos.6,288,234, 6,090,912, 5,840,485, each of which is hereby incorporated byreference in its entirety, including all charts and drawings.

In various embodiments, the present invention provides methods ofdesigning ligands that bind to a plurality of members of a molecularfamily, where the ligands contain a common molecular scaffold. Thus, acompound set can be assayed for binding to a plurality of members of amolecular family, e.g., a protein family. One or more compounds thatbind to a plurality of family members can be identified as molecularscaffolds. When the orientation of the scaffold at the binding site ofthe target molecules has been determined and chemically tractablestructures have been identified, a set of ligands can be synthesizedstarting with one or a few molecular scaffolds to arrive at a pluralityof ligands, wherein each ligand binds to a separate target molecule ofthe molecular family with altered or changed binding affinity or bindingspecificity relative to the scaffold. Thus, a plurality of drug leadmolecules can be designed to individually target members of a molecularfamily based on the same molecular scaffold, and act on them in aspecific manner.

D. Binding Assays

1. Use of Binding Assays

The methods of the present invention can involve assays that are able todetect the binding of compounds to a target molecule at a signal of atleast about three times the standard deviation of the background signal,or at least about four times the standard deviation of the backgroundsignal. The assays can also include assaying compounds for low affinitybinding to the target molecule. A large variety of assays indicative ofbinding are known for different target types and can be used for thisinvention. Compounds that act broadly across protein families are notlikely to have a high affinity against individual targets, due to thebroad nature of their binding. Thus, assays (e.g., as described herein)highly preferably allow for the identification of compounds that bindwith low affinity, very low affinity, and extremely low affinity.Therefore, potency (or binding affinity) is not the primary, nor eventhe most important, indicia of identification of a potentially usefulbinding compound. Rather, even those compounds that bind with lowaffinity, very low affinity, or extremely low affinity can be consideredas molecular scaffolds that can continue to the next phase of the liganddesign process.

As indicated above, to design or discover scaffolds that act broadlyacross protein families, proteins of interest can be assayed against acompound collection or set. The assays can preferably be enzymatic orbinding assays. In some embodiments it may be desirable to enhance thesolubility of the compounds being screened and then analyze allcompounds that show activity in the assay, including those that bindwith low affinity or produce a signal with greater than about threetimes the standard deviation of the background signal. These assays canbe any suitable assay such as, for example, binding assays that measurethe binding affinity between two binding partners. Various types ofscreening assays that can be useful in the practice of the presentinvention are known in the art, such as those described in U.S. Pat.Nos. 5,763,198, 5,747,276, 5,877,007, 6,243,980, 6,294,330, and6,294,330, each of which is hereby incorporated by reference in itsentirety, including all charts and drawings.

In various embodiments of the assays at least one compound, at leastabout 5%, at least about 10%, at least about 15%, at least about 20%, orat least about 25% of the compounds can bind with low affinity. In manycases, up to about 20% of the compounds can show activity in thescreening assay and these compounds can then be analyzed directly withhigh-throughput co-crystallography, computational analysis to group thecompounds into classes with common structural properties (e.g.,structural core and/or shape and polarity characteristics), and theidentification of common chemical structures between compounds that showactivity.

The person of ordinary skill in the art will realize that decisions canbe based on criteria that are appropriate for the needs of theparticular situation, and that the decisions can be made by computersoftware programs. Classes can be created containing almost any numberof scaffolds, and the criteria selected can be based on increasinglyexacting criteria until an arbitrary number of scaffolds is arrived atfor each class that is deemed to be advantageous.

2. Surface Plasmon Resonance

Binding parameters can be measured using surface plasmon resonance, forexample, with a BIAcore® chip (Biacore, Japan) coated with immobilizedbinding components. Surface plasmon resonance is used to characterizethe microscopic association and dissociation constants of reactionbetween an sFv or other ligand directed against target molecules. Suchmethods are generally described in the following references which areincorporated herein by reference. Vely F. et al., BIAcore® analysis totest phosphopeptide-SH2 domain interactions, Methods in MolecularBiology. 121:313-21, 2000; Liparoto et al., Biosensor analysis of theinterleukin-2 receptor complex, Journal of Molecular Recognition.12:316-21, 1999; Lipschultz et al., Experimental design for analysis ofcomplex kinetics using surface plasmon resonance, Methods. 20(3):310-8,2000; Malmqvist., BIACORE: an affinity biosensor system forcharacterization of biomolecular interactions, Biochemical SocietyTransactions 27:335-40, 1999; Alfthan, Surface plasmon resonancebiosensors as a tool in antibody engineering, Biosensors &Bioelectronics. 13:653-63, 1998; Fivash et al., BIAcore formacromolecular interaction, Current Opinion in Biotechnology. 9:97-101,1998; Price et al.; Summary report on the ISOBM TD-4 Workshop: analysisof 56 monoclonal antibodies against the MUC1 mucin. Tumour Biology 19Suppl 1:1-20, 1998; Malmqvist et al, Biomolecular interaction analysis:affinity biosensor technologies for functional analysis of proteins,Current Opinion in Chemical Biology. 1:378-83, 1997; O'Shannessy et al.,Interpretation of deviations from pseudo-first-order kinetic behavior inthe characterization of ligand binding by biosensor technology,Analytical Biochemistry. 236:275-83, 1996; Malmborg et al., BIAcore as atool in antibody engineering, Journal of Immunological Methods.183:7-13, 1995; Van Regenmortel, Use of biosensors to characterizerecombinant proteins, Developments in Biological Standardization.83:143-51, 1994; and O' Shannessy, Determination of kinetic rate andequilibrium binding constants for macromolecular interactions: acritique of the surface plasmon resonance literature, Current Opinionsin Biotechnology. 5:65-71, 1994.

BIAcore® uses the optical properties of surface plasmon resonance (SPR)to detect alterations in protein concentration bound to a dextran matrixlying on the surface of a gold/glass sensor chip interface, a dextranbiosensor matrix. In brief, proteins are covalently bound to the dextranmatrix at a known concentration and a ligand for the protein is injectedthrough the dextran matrix. Near infrared light, directed onto theopposite side of the sensor chip surface is reflected and also inducesan evanescent wave in the gold film, which in turn, causes an intensitydip in the reflected light at a particular angle known as the resonanceangle. If the refractive index of the sensor chip surface is altered(e.g., by ligand binding to the bound protein) a shift occurs in theresonance angle. This angle shift can be measured and is expressed asresonance units (RUs) such that 1000 RUs is equivalent to a change insurface protein concentration of 1 ng/mm². These changes are displayedwith respect to time along the y-axis of a sensorgram, which depicts theassociation and dissociation of any biological reaction.

E. High Throughput Screening (HTS) Assays

HTS typically uses automated assays to search through large numbers ofcompounds for a desired activity. Typically HTS assays are used to findnew drugs by screening for chemicals that act on a particular enzyme ormolecule. For example, if a chemical inactivates an enzyme it mightprove to be effective in preventing a process in a cell which causes adisease. High throughput methods enable researchers to assay thousandsof different chemicals against each target molecule very quickly usingrobotic handling systems and automated analysis of results.

As used herein, “high throughput screening” or “HTS” refers to the rapidin vitro screening of large numbers of compounds (libraries); generallytens to hundreds of thousands of compounds, using robotic screeningassays. Ultra high-throughput Screening (uHTS) generally refers to thehigh-throughput screening accelerated to greater than 100,000 tests perday.

To achieve high-throughput screening, it is advantageous to housesamples on a multicontainer carrier or platform. A multicontainercarrier facilitates measuring reactions of a plurality of candidatecompounds simultaneously. Multi-well microplates may be used as thecarrier. Such multi-well microplates, and methods for their use innumerous assays, are both known in the art and commercially available.

Screening assays may include controls for purposes of calibration andconfirmation of proper manipulation of the components of the assay.Blank wells that contain all of the reactants but no member of thechemical library are usually included. As another example, a knowninhibitor (or activator) of an enzyme for which modulators are sought,can be incubated with one sample of the assay, and the resultingdecrease (or increase) in the enzyme activity used as a comparator orcontrol. It will be appreciated that modulators can also be combinedwith the enzyme activators or inhibitors to find modulators whichinhibit the enzyme activation or repression that is otherwise caused bythe presence of the known the enzyme modulator. Similarly, when ligandsto a target are sought, known ligands of the target can be present incontrol/calibration assay wells.

F. Measuring Enzymatic and Binding Reactions During Screening Assays

Techniques for measuring the progression of enzymatic and bindingreactions, e.g., in multicontainer carriers, are known in the art andinclude, but are not limited to, the following.

Spectrophotometric and spectrofluorometric assays are well known in theart. Examples of such assays include the use of colorimetric assays forthe detection of peroxides, as described in Gordon, A. J. and Ford, R.A., The Chemist's Companion: A Handbook Of Practical Data, Techniques,And References, John Wiley and Sons, N.Y., 1972, Page 437.

Fluorescence spectrometry may be used to monitor the generation ofreaction products. Fluorescence methodology is generally more sensitivethan the absorption methodology. The use of fluorescent probes is wellknown to those skilled in the art. For reviews, see Bashford et al.,Spectrophotometry and Spectrofluorometry: A Practical Approach, pp.91-114, IRL Press Ltd. (1987); and Bell, Spectroscopy In Biochemistry,Vol. I, pp. 155-194, CRC Press (1981).

In spectrofluorometric methods, enzymes are exposed to substrates thatchange their intrinsic fluorescence when processed by the target enzyme.Typically, the substrate is nonfluorescent and is converted to afluorophore through one or more reactions. As a non-limiting example,SMase activity can be detected using the Amplex® Red reagent (MolecularProbes, Eugene, Oreg.). In order to measure sphingomyelinase activityusing Amplex® Red, the following reactions occur. First, SMasehydrolyzes sphingomyelin to yield ceramide and phosphorylcholine.Second, alkaline phosphatase hydrolyzes phosphorylcholine to yieldcholine. Third, choline is oxidized by choline oxidase to betaine.Finally, H₂O₂, in the presence of horseradish peroxidase, reacts withAmplex® Red to produce the fluorescent product, Resorufin, and thesignal therefrom is detected using spectrofluorometry.

Fluorescence polarization (FP) is based on a decrease in the speed ofmolecular rotation of a fluorophore that occurs upon binding to a largermolecule, such as a receptor protein, allowing for polarized fluorescentemission by the bound ligand. FP is empirically determined by measuringthe vertical and horizontal components of fluorophore emission followingexcitation with plane polarized light. Polarized emission is increasedwhen the molecular rotation of a fluorophore is reduced. A fluorophoreproduces a larger polarized signal when it is bound to a larger molecule(i.e. a receptor), slowing molecular rotation of the fluorophore. Themagnitude of the polarized signal relates quantitatively to the extentof fluorescent ligand binding. Accordingly, polarization of the “bound”signal depends on maintenance of high affinity binding.

FP is a homogeneous technology and reactions are very rapid, takingseconds to minutes to reach equilibrium. The reagents are stable, andlarge batches may be prepared, resulting in high reproducibility.Because of these properties, FP has proven to be highly automatable,often performed with a single incubation with a single, premixed,tracer-receptor reagent. For a review, see Owickiet al., Application ofFluorescence Polarization Assays in High-Throughput Screening, GeneticEngineering News, 17:27, 1997.

FP is particularly desirable since its readout is independent of theemission intensity (Checovich, W. J., et al., Nature 375:254-256, 1995;Dandliker, W. B., et al., Methods in Enzymology 74:3-28, 1981) and isthus insensitive to the presence of colored compounds that quenchfluorescence emission. FP and FRET (see below) are well-suited foridentifying compounds that block interactions between sphingolipidreceptors and their ligands. See, for example, Parker et al.,Development of high throughput screening assays using fluorescencepolarization: nuclear receptor-ligand-binding and kinase/phosphataseassays, J Biomol Screen 5:77-88, 2000.

Fluorophores derived from sphingolipids that may be used in FP assaysare commercially available. For example, Molecular Probes (Eugene,Oreg.) currently sells sphingomyelin and one ceramide fluorophores.These are, respectively,N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl)sphingosylphosphocholine (BODIPY® FL C5-sphingomyelin);N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-dodecanoyl)sphingosylphosphocholine (BODIPY® FL C12-sphingomyelin); andN-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl)sphingosine(BODIPY® FL C5-ceramide). U.S. Pat. No. 4,150,949, (Immunoassay forgentamicin), discloses fluorescein-labelled gentamicins, includingfluoresceinthiocarbanyl gentamicin. Additional fluorophores may beprepared using methods well known to the skilled artisan.

Exemplary normal-and-polarized fluorescence readers include thePOLARION® fluorescence polarization system (Tecan AG, Hombrechtikon,Switzerland). General multiwell plate readers for other assays areavailable, such as the VERSAMAX® reader and the SPECTRAMAX® multiwellplate spectrophotometer (both from Molecular Devices).

Fluorescence resonance energy transfer (FRET) is another useful assayfor detecting interaction and has been described. See, e.g., Heim etal., Curr. Biol. 6:178-182, 1996; Mitra et al., Gene 173:13-17 1996; andSelvin et al., Meth. Enzymol. 246:300-345, 1995. FRET detects thetransfer of energy between two fluorescent substances in closeproximity, having known excitation and emission wavelengths. As anexample, a protein can be expressed as a fusion protein with greenfluorescent protein (GFP). When two fluorescent proteins are inproximity, such as when a protein specifically interacts with a targetmolecule, the resonance energy can be transferred from one excitedmolecule to the other. As a result, the emission spectrum of the sampleshifts, which can be measured by a fluorometer, such as a fMAX multiwellfluorometer (Molecular Devices, Sunnyvale Calif.).

Scintillation proximity assay (SPA) is a particularly useful assay fordetecting an interaction with the target molecule. SPA is widely used inthe pharmaceutical industry and has been described (Hanselman et al., J.Lipid Res. 38:2365-2373 (1997); Kahl et al., Anal. Biochem. 243:282-283(1996); Undenfriend et al., Anal. Biochem. 161:494-500 (1987)). See alsoU.S. Pat. Nos. 4,626,513 and 4,568,649, and European Patent No.0,154,734. One commercially available system uses FLASHPLATE®scintillant-coated plates (NEN Life Science Products, Boston, Mass.).

The target molecule can be bound to the scintillator plates by a varietyof well known means. Scintillant plates are available that arederivatized to bind to fusion proteins such as GST, His6 or Flag fusionproteins. Where the target molecule is a protein complex or a multimer,one protein or subunit can be attached to the plate first, then theother components of the complex added later under binding conditions,resulting in a bound complex.

In a typical SPA assay, the gene products in the expression pool willhave been radiolabeled and added to the wells, and allowed to interactwith the solid phase, which is the immobilized target molecule andscintillant coating in the wells. The assay can be measured immediatelyor allowed to reach equilibrium. Either way, when a radiolabel becomessufficiently close to the scintillant coating, it produces a signaldetectable by a device such as a TOPCOUNT NXT® microplate scintillationcounter (Packard BioScience Co., Meriden Conn.). If a radiolabeledexpression product binds to the target molecule, the radiolabel remainsin proximity to the scintillant long enough to produce a detectablesignal.

In contrast, the labeled proteins that do not bind to the targetmolecule, or bind only briefly, will not remain near the scintillantlong enough to produce a signal above background. Any time spent nearthe scintillant caused by random Brownian motion will also not result ina significant amount of signal. Likewise, residual unincorporatedradiolabel used during the expression step may be present, but will notgenerate significant signal because it will be in solution rather thaninteracting with the target molecule. These non-binding interactionswill therefore cause a certain level of background signal that can bemathematically removed. If too many signals are obtained, salt or othermodifiers can be added directly to the assay plates until the desiredspecificity is obtained (Nichols et al., Anal. Biochem. 257:112-119,1998).

Additionally, the assay can utilize AlphaScreen (amplified luminescentproximity homogeneous assay) format, e.g., AlphaScreening system(Packard BioScience). AlphaScreen is generally described in Seethala andPrabhavathi, Homogenous Assays: AlphaScreen, Handbook of Drug Screening,Marcel Dekkar Pub. 2001, pp. 106-110. Applications of the technique toPPAR receptor ligand binding assays are described, for example, in Xu etal., 2002, Nature 415:813-817.

G. Assay Compounds and Molecular Scaffolds

As described above, preferred characteristics of a scaffold includebeing of low molecular weight (e.g., less than 350 Da, or from about 100to about 350 daltons, or from about 150 to about 300 daltons).Preferably clog P of a scaffold is from −1 to 8, more preferably lessthan 6, 5, or 4, most preferably less than 3. In particular embodimentsthe clogP is in a range −1 to an upper limit of 2, 3, 4, 5, 6, or 8; oris in a range of 0 to an upper limit of 2, 3, 4, 5, 6, or 8. Preferablythe number of rotatable bonds is less than 5, more preferably less than4. Preferably the number of hydrogen bond donors and acceptors is below6, more preferably below 5. An additional criterion that can be usefulis a Polar Surface Area of less than 100. Guidance that can be useful inidentifying criteria for a particular application can be found inLipinski et al., Advanced Drug Delivery Reviews 23 (1997) 3-25, which ishereby incorporated by reference in its entirety.

A scaffold will preferably bind to a given protein binding site in aconfiguration that causes substituent moieties of the scaffold to besituated in pockets of the protein binding site. Also, possessingchemically tractable groups that can be chemically modified,particularly through synthetic reactions, to easily create acombinatorial library can be a preferred characteristic of the scaffold.Also preferred can be having positions on the scaffold to which othermoieties can be attached, which do not interfere with binding of thescaffold to the protein(s) of interest but do cause the scaffold toachieve a desirable property, for example, active transport of thescaffold to cells and/or organs, enabling the scaffold to be attached toa chromatographic column to facilitate analysis, or another desirableproperty. A molecular scaffold can bind to a target molecule with anyaffinity, such as binding with an affinity measurable as about threetimes the standard deviation of the background signal, or at highaffinity, moderate affinity, low affinity, very low affinity, orextremely low affinity.

Thus, the above criteria can be utilized to select many compounds fortesting that have the desired attributes. Many compounds having thecriteria described are available in the commercial market, and may beselected for assaying depending on the specific needs to which themethods are to be applied. In some cases sufficiently large numbers ofcompounds may meet specific criteria that additional methods to groupsimilar compounds may be helpful. A variety of methods to assessmolecular similarity, such as the Tanimoto coefficient have been used,see Willett et al, Journal of Chemical Information and Computer Science38 (1998), 983-996. These can be used to select a smaller subset of agroup of highly structurally redundant compounds. In addition, clusteranalysis based on relationships between the compounds, or structuralcomponents of the compound, can also be carried out to the same end; seeLance and Williams Computer Journal 9 (1967) 373-380, Jarvis and PatrickIEEE Transactions in Computers C-22 (1973) 1025-1034 for clusteringalgorithms, and Downs et al. Journal of Chemical Information andComputer Sciences 34 (1994) 1094-1102 for a review of these methodsapplied to chemical problems. One method of deriving the chemicalcomponents of a large group of potential scaffolds is to virtually breakup the compound at rotatable bonds so as to yield components of no lessthan 10 atoms. The resulting components may be clustered based on somemeasure of similarity, e.g. the Tanimoto coefficient, to yield thecommon component groups in the original collection of compounds. Foreach component group, all compounds containing that component may beclustered, and the resulting clusters used to select a diverse set ofcompounds containing a common chemical core structure. In this fashion,a useful library of scaffolds may be derived even from millions ofcommercial compounds.

A “compound library” or “library” is a collection of different compoundshaving different chemical structures. A compound library is screenable,that is, the compound library members therein may be subject toscreening assays. In preferred embodiments, the library members can havea molecular weight of from about 100 to about 350 daltons, or from about150 to about 350 daltons.

Libraries can contain at least one compound that binds to the targetmolecule at low affinity. Libraries of candidate compounds can beassayed by many different assays, such as those described above, e.g., afluorescence polarization assay. Libraries may consist of chemicallysynthesized peptides, peptidomimetics, or arrays of combinatorialchemicals that are large or small, focused or nonfocused. By “focused”it is meant that the collection of compounds is prepared using thestructure of previously characterized compounds and/or pharmacophores.

Compound libraries may contain molecules isolated from natural sources,artificially synthesized molecules, or molecules synthesized, isolated,or otherwise prepared in such a manner so as to have one or moremoieties variable, e.g., moieties that are independently isolated orrandomly synthesized. Types of molecules in compound libraries includebut are not limited to organic compounds, polypeptides and nucleic acidsas those terms are used herein, and derivatives, conjugates and mixturesthereof.

Compound libraries useful for the invention may be purchased on thecommercial market or prepared or obtained by any means including, butnot limited to, combinatorial chemistry techniques, fermentationmethods, plant and cellular extraction procedures and the like (see,e.g., Cwirla et al., Biochemistry 1990, 87, 6378-6382; Houghten et al.,Nature 1991, 354, 84-86; Lam et al., Nature 1991, 354, 82-84; Brenner etal., Proc. Natl. Acad. Sci. USA 1992, 89, 5381-5383; R. A. Houghten,Trends Genet. 1993, 9, 235-239; E. R. Felder, Chimia 1994, 48, 512-541;Gallop et al., J. Med. Chem. 1994, 37, 1233-1251; Gordon et al., J. Med.Chem. 1994, 37, 1385-1401; Carell et al., Chem. Biol. 1995, 3, 171-183;Madden et al., Perspectives in Drug Discovery and Design 2, 269-282;Lebl et al., Biopolymers 1995, 37 177-198); small molecules assembledaround a shared molecular structure; collections of chemicals that havebeen assembled by various commercial and noncommercial groups, naturalproducts; extracts of marine organisms, fungi, bacteria, and plants.

Preferred libraries can be prepared in a homogenous reaction mixture,and separation of unreacted reagents from members of the library is notrequired prior to screening. Although many combinatorial chemistryapproaches are based on solid state chemistry, liquid phasecombinatorial chemistry is capable of generating libraries (Sun C M.,Recent advances in liquid-phase combinatorial chemistry, CombinatorialChemistry & High Throughput Screening. 2:299-318, 1999).

Libraries of a variety of types of molecules are prepared in order toobtain members therefrom having one or more preselected attributes thatcan be prepared by a variety of techniques, including but not limited toparallel array synthesis (Houghton, Annu Rev Pharmacol Toxicol 200040:273-82, Parallel array and mixture-based synthetic combinatorialchemistry; solution-phase combinatorial chemistry (Merritt, Comb ChemHigh Throughput Screen 1998 1(2):57-72, Solution phase combinatorialchemistry, Coe et al., Mol Divers 1998-99; 4(1):31-8, Solution-phasecombinatorial chemistry, Sun, Comb Chem High Throughput Screen 19992(6):299-318, Recent advances in liquid-phase combinatorial chemistry);synthesis on soluble polymer (Gravert et al., Curr Opin Chem Biol 19971(1):107-13, Synthesis on soluble polymers: new reactions and theconstruction of small molecules); and the like. See, e.g., Dolle et al.,J Comb Chem 1999 1(4):235-82, Comprehensive survey of cominatoriallibrary synthesis: 1998. Freidinger R M., Nonpeptidic ligands forpeptide and protein receptors, Current Opinion in Chemical Biology; andKundu et al., Prog Drug Res 1999; 53:89-156, Combinatorial chemistry:polymer supported synthesis of peptide and non-peptide libraries).Compounds may be clinically tagged for ease of identification (Chabala,Curr Opin Biotechnol 1995 6(6):633-9, Solid-phase combinatorialchemistry and novel tagging methods for identifying leads).

The combinatorial synthesis of carbohydrates and libraries containingoligosaccharides have been described (Schweizer et al., Curr Opin ChemBiol 1999 3(3):291-8, Combinatorial synthesis of carbohydrates). Thesynthesis of natural-product based compound libraries has been described(Wessjohann, Curr Opin Chem Biol 2000 4(3):303-9, Synthesis ofnatural-product based compound libraries).

Libraries of nucleic acids are prepared by various techniques, includingby way of non-limiting example the ones described herein, for theisolation of aptamers. Libraries that include oligonucleotides andpolyaminooligonucleotides (Markiewicz et al., Synthetic oligonucleotidecombinatorial libraries and their applications, Farmaco. 55:174-7, 2000)displayed on streptavidin magnetic beads are known. Nucleic acidlibraries are known that can be coupled to parallel sampling and bedeconvoluted without complex procedures such as automated massspectrometry (Enjalbal C. Martinez J. Aubagnac J L, Mass spectrometry incombinatorial chemistry, Mass Spectrometry Reviews. 19:139-61, 2000) andparallel tagging. (Perrin D M., Nucleic acids for recognition andcatalysis: landmarks, limitations, and looking to the future,Combinatorial Chemistry & High Throughput Screening 3:243-69).

Peptidomimetics are identified using combinatorial chemistry and solidphase synthesis (Kim H O. Kahn M., A merger of rational drug design andcombinatorial chemistry: development and application of peptidesecondary structure mimetics, Combinatorial Chemistry & High ThroughputScreening 3:167-83, 2000; al-Obeidi, Mol Biotechnol 1998 9(3):205-23,Peptide and peptidomimetric libraries. Molecular diversity and drugdesign). The synthesis may be entirely random or based in part on aknown polypeptide.

Polypeptide libraries can be prepared according to various techniques.In brief, phage display techniques can be used to produce polypeptideligands (Gram H., Phage display in proteolysis and signal transduction,Combinatorial Chemistry & High Throughput Screening. 2:19-28, 1999) thatmay be used as the basis for synthesis of peptidomimetics. Polypeptides,constrained peptides, proteins, protein domains, antibodies, singlechain antibody fragments, antibody fragments, and antibody combiningregions are displayed on filamentous phage for selection.

Large libraries of individual variants of human single chain Fvantibodies have been produced. See, e.g., Siegel R W. Allen B. Pavlik P.Marks J D. Bradbury A., Mass spectral analysis of a protein complexusing single-chain antibodies selected on a peptide target: applicationsto functional genomics, Journal of Molecular Biology 302:285-93, 2000;Poul M A. Becerril B. Nielsen U B. Morisson P. Marks J D., Selection oftumor-specific internalizing human antibodies from phage libraries.Source Journal of Molecular Biology. 301:1149-61, 2000; Amersdorfer P.Marks J D., Phage libraries for generation of anti-botulinum scFvantibodies, Methods in Molecular Biology. 145:219-40, 2001; Hughes-JonesN C. Bye J M. Gorick B D. Marks J D. Ouwehand W H., Synthesis of Rh Fvphage-antibodies using VH and VL germline genes, British Journal ofHaematology. 105:811-6, 1999; McCall A M. Amoroso A R. Sautes C. Marks JD. Weiner L M., Characterization of anti-mouse Fc gamma RII single-chainFv fragments derived from human phage display libraries,Immunotechnology. 4:71-87, 1998; Sheets M D. Amersdorfer P. Finnern R.Sargent P. Lindquist E. Schier R. Hemingsen G. Wong C. Gerhart J C.Marks J D. Lindquist E., Efficient construction of a large nonimmunephage antibody library: the production of high-affinity humansingle-chain antibodies to protein antigens (published erratum appearsin Proc Natl Acad Sci USA 1999 96:795), Proc Natl Acad Sci USA95:6157-62, 1998).

Focused or smart chemical and pharmacophore libraries can be designedwith the help of sophisticated strategies involving computationalchemistry (e.g., Kundu B. Khare S K. Rastogi S K., Combinatorialchemistry: polymer supported synthesis of peptide and non-peptidelibraries, Progress in Drug Research 53:89-156, 1999) and the use ofstructure-based ligands using database searching and docking, de novodrug design and estimation of ligand binding affinities (Joseph-McCarthyD., Computational approaches to structure-based ligand design,Pharmacology & Therapeutics 84:179-91, 1999; Kirkpatrick D L. Watson S.Ulhaq S., Structure-based drug design: combinatorial chemistry andmolecular modeling, Combinatorial Chemistry & High Throughput Screening.2:211-21, 1999; Eliseev A V. Lehn J M., Dynamic combinatorial chemistry:evolutionary formation and screening of molecular libraries, CurrentTopics in Microbiology & Immunology 243:159-72, 1999; Bolger et al.,Methods Enz. 203:21-45, 1991; Martin, Methods Enz. 203:587-613, 1991;Neidle et al., Methods Enz. 203:433-458, 1991; U.S. Pat. No. 6,178,384).

Selecting a library of potential scaffolds and a set of assays measuringbinding to representative target molecules which are in a particularprotein family thus allows the creation of a data set profiling bindingof the library to the target protein family. Groups of scaffolds withdifferent sets of binding properties can be identified using theinformation within this dataset. Thus, groups of scaffolds binding toone, two or three members of the family may be selected for particularapplications.

In many cases, a group of scaffolds exhibiting binding to two or moremembers of a target protein family will contain scaffolds with a greaterlikelihood that such binding results from specific interactions with theindividual target proteins. This would be expected to substantiallyreduce the effect of so-called “promiscuous inhibitors” which severelycomplicate the interpretation of screening assays (see McGovern et alJournal of Medicinal Chemistry 45:1712-22, 2002). Thus, in manypreferred applications the property of displaying binding to multipletarget molecules in a protein family may be used as a selection criteriato identify molecules with desirable properties. In addition, groups ofscaffolds binding to specific subsets of a set of potential targetmolecules may be selected. Such a case would include the subset ofscaffolds that bind to any two of three or three of five members of atarget protein family.

Such subsets may also be used in combination or opposition to furtherdefine a group of scaffolds that have additional desirable properties.This would be of significant utility in cases where inhibiting somemembers of a protein family had known desirable effects, such asinhibiting tumor growth, whereas inhibiting other members of the proteinfamily which were found to be essential for normal cell function wouldhave undesirable effects. A criteria that would be useful in such a caseincludes selecting the subset of scaffolds binding to any two of threedesirable target molecules and eliminating from this group any thatbound to more than one of any three undesirable target molecules.

H. Crystallography

After binding compounds have been determined, the orientation ofcompound bound to target is determined. Preferably this determinationinvolves crystallography on co-crystals of molecular scaffold compoundswith target. Most protein crystallographic platforms can preferably bedesigned to analyze up to about 500 co-complexes of compounds, ligands,or molecular scaffolds bound to protein targets due to the physicalparameters of the instruments and convenience of operation.

If the number of scaffolds that have binding activity exceeds a numberconvenient for the application of crystallography methods, the scaffoldscan be placed into groups based on having at least one common chemicalstructure or other desirable characteristics, and representativecompounds can be selected from one or more of the classes. Classes canbe made with increasingly exacting criteria until a desired number ofclasses (e.g., 10, 20, 50, 100, 200, 300, 400, 500) is obtained. Theclasses can be based on chemical structure similarities betweenmolecular scaffolds in the class, e.g., all possess a pyrrole ring,benzene ring, or other chemical feature. Likewise, classes can be basedon shape characteristics, e.g., space-filling characteristics.

The co-crystallography analysis can be performed by co-complexing eachscaffold with its target, e.g., at concentrations of the scaffold thatshowed activity in the screening assay. This co-complexing can, forexample, be accomplished with the use of low percentage organic solventswith the target molecule and then concentrating the target with each ofthe scaffolds. In preferred embodiments these solvents are less than 5%organic solvent such as dimethyl sulfoxide (DMSO), ethanol, methanol, orethylene glycol in water or another aqueous solvent.

Each scaffold complexed to the target molecule can then be screened witha suitable number of crystallization screening conditions at appropriatetemperature, e.g., both 4 and 20 degrees. In preferred embodiments,about 96 crystallization screening conditions can be performed in orderto obtain sufficient information about the co-complexation andcrystallization conditions, and the orientation of the scaffold at thebinding site of the target molecule. Crystal structures can then beanalyzed to determine how the bound scaffold is oriented physicallywithin the binding site or within one or more binding pockets of themolecular family member.

It is desirable to determine the atomic coordinates of the compoundsbound to the target proteins in order to determine which is a mostsuitable scaffold for the protein family. X-ray crystallographicanalysis is therefore most preferable for determining the atomiccoordinates. Those compounds selected can be further tested with theapplication of medicinal chemistry. Compounds can be selected formedicinal chemistry testing based on their binding position in thetarget molecule. For example, when the compound binds at a binding site,the compound's binding position in the binding site of the targetmolecule can be considered with respect to the chemistry that can beperformed on chemically tractable structures or sub-structures of thecompound, and how such modifications on the compound are expected tointeract with structures or sub-structures on the binding site of thetarget. Thus, one can explore the binding site of the target and thechemistry of the scaffold in order to make decisions on how to modifythe scaffold to arrive at a ligand with higher potency and/orselectivity.

The structure of the target molecule bound to the compound may also besuperimposed or aligned with other structures of members of the sameprotein family. In this way modifications of the scaffold can be made toenhance the binding to members of the target family in general, thusenhancing the utility of the scaffold library. Different usefulalignments may be generated, using a variety of criteria such as minimalRMSD superposition of alpha-carbons or backbone atoms of homologous orstructurally related regions of the proteins.

These processes allow for more direct design of ligands, by utilizingstructural and chemical information obtained directly from theco-complex, thereby enabling one to more efficiently and quickly designlead compounds that are likely to lead to beneficial drug products. Invarious embodiments it may be desirable to perform co-crystallography onall scaffolds that bind, or only those that bind with a particularaffinity, for example, only those that bind with high affinity, moderateaffinity, low affinity, very low affinity, or extremely low affinity. Itmay also be advantageous to perform co-crystallography on a selection ofscaffolds that bind with any combination of affinities.

Standard X-ray protein diffraction studies such as by using a RigakuRU-200® (Rigaku, Tokyo, Japan) with an X-ray imaging plate detector or asynchrotron beam-line can be performed on co-crystals and thediffraction data measured on a standard X-ray detector, such as a CCDdetector or an X-ray imaging plate detector.

Performing X-ray crystallography on about 200 co-crystals shouldgenerally lead to about 50 co-crystal structures, which should provideabout 10 scaffolds for validation in chemistry, which should finallyresult in about 5 selective leads for target molecules.

Additives that promote co-crystallization can of course be included inthe target molecule formulation in order to enhance the formation ofco-crystals. In the case of proteins or enzymes, the scaffold to betested can be added to the protein formulation, which is preferablypresent at a concentration of approximately 1 mg/ml. The formulation canalso contain between 0%-10% (v/v) organic solvent, e.g. DMSO, methanol,ethanol, propane diol, or 1,3 dimethyl propane diol (MPD) or somecombination of those organic solvents. Compounds are preferablysolubilized in the organic solvent at a concentration of about 10 mM andadded to the protein sample at a concentration of about 100 mM. Theprotein-compound complex is then concentrated to a final concentrationof protein of from about 5 to about 20 mg/ml. The complexation andconcentration steps can conveniently be performed using a 96 wellformatted concentration apparatus (e.g., Amicon Inc., Piscataway, N.J.).Buffers and other reagents present in the formulation being crystallizedcan contain other components that promote crystallization or arecompatible with crystallization conditions, such as DTT, propane diol,glycerol.

The crystallization experiment can be set-up by placing small aliquotsof the concentrated protein-compound complex (e.g., 1 μl) in a 96 wellformat and sampling under 96 crystallization conditions. (Other formatscan also be used, for example, plates with fewer or more wells.)Crystals can typically be obtained using standard crystallizationprotocols that can involve the 96 well crystallization plate beingplaced at different temperatures. Co-crystallization varying factorsother than temperature can also be considered for each protein-compoundcomplex if desirable. For example, atmospheric pressure, the presence orabsence of light or oxygen, a change in gravity, and many othervariables can all be tested. The person of ordinary skill in the artwill realize other variables that can advantageously be varied andconsidered. Conveniently, commercially available crystal screeningplates with specified conditions in individual wells can be utilized.

I. Virtual Assays

As described above, virtual assays or compound design techniques areuseful for identification and design of modulators; such techniques arealso applicable to a molecular scaffold method. Commercially availablesoftware that generates three-dimensional graphical representations ofthe complexed target and compound from a set of coordinates provided canbe used to illustrate and study how a compound is oriented when bound toa target. (e.g., InsightII®, Accelerys, San Diego, Calif.; or Sybyl®,Tripos Associates, St. Louis, Mo.). Thus, the existence of bindingpockets at the binding site of the targets can be particularly useful inthe present invention. These binding pockets are revealed by thecrystallographic structure determination and show the precise chemicalinteractions involved in binding the compound to the binding site of thetarget. The person of ordinary skill will realize that the illustrationscan also be used to decide where chemical groups might be added,substituted, modified, or deleted from the scaffold to enhance bindingor another desirable effect, by considering where unoccupied space islocated in the complex and which chemical substructures might havesuitable size and/or charge characteristics to fill it. The person ofordinary skill will also realize that regions within the binding sitecan be flexible and its properties can change as a result of scaffoldbinding, and that chemical groups can be specifically targeted to thoseregions to achieve a desired effect. Specific locations on the molecularscaffold can be considered with reference to where a suitable chemicalsubstructure can be attached and in which conformation, and which sitehas the most advantageous chemistry available.

An understanding of the forces that bind the compounds to the targetproteins reveals which compounds can most advantageously be used asscaffolds, and which properties can most effectively be manipulated inthe design of ligands. The person of ordinary skill will realize thatsteric, ionic, polar, hydrogen bond, and other forces can be consideredfor their contribution to the maintenance or enhancement of thetarget-compound complex. Additional data can be obtained with automatedcomputational methods, such as docking and/or molecular dynamicssimulations, which can afford a measure of the energy of binding. Inaddition, to account for other effects such as entropies of binding anddesolvation penalties, methods which provide a measure of these effectscan be integrated into the automated computational approach. Thecompounds selected can be used to generate information about thechemical interactions with the target or for elucidating chemicalmodifications that can enhance selectivity of binding of the compound.

An exemplary calculation of binding energies between protein-ligandcomplexes can be obtained using the FlexX score (an implementation ofthe Bohm scoring function) within the Tripos software suite (TriposAssociates, St. Louis, Mo.). The form for that equation is shown below:

ΔGbind=ΔGtr+ΔGhb+ΔGion+ΔGlipo+ΔGarom+ΔGrot

where: ΔGtr is a constant term that accounts for the overall loss ofrotational and translational entropy of the ligand, ΔGhb accounts forhydrogen bonds formed between the ligand and protein, ΔGion accounts forthe ionic interactions between the ligand and protein, ΔGlipo accountsfor the lipophilic interaction that corresponds to the protein-ligandcontact surface, ΔGarom accounts for interactions between aromatic ringsin the protein and ligand, and ΔGrot accounts for the entropic penaltyof restricting rotatable bonds in the ligand upon binding. Thecalculated binding energy for compounds that bind strongly to a giventarget will likely be lower than −25 kcal/mol, while the calculatedbinding affinity for a good scaffold or an unoptimized compound willgenerally be in the range of −15 to −20. The penalty for restricting alinker such as the ethylene glycol or hexatriene is estimated astypically being in the range of +5 to +15.

This method estimates the free energy of binding that a lead compoundshould have to a target protein for which there is a crystal structure,and it accounts for the entropic penalty of flexible linkers. It cantherefore be used to estimate the penalty incurred by attaching linkersto molecules being screened and the binding energy that a lead compoundmust attain in order to overcome the penalty of the linker. The methoddoes not account for solvation, and the entropic penalty is likelyoverestimated when the linkers are bound to the solid phase through anadditional binding complex, e.g., a biotin:streptavidin complex.

Another exemplary method for calculating binding energies is the MM-PBSAtechnique (Massova and Kollman, Journal of the American Chemical Society121:8133-43, 1999; Chong et al, Proceedings of the National Academy ofSciences 96:14330-5, 1999; Donini and Kollman, Journal of MedicinalChemistry 43:4180-8, 2000). This method uses a Molecular Dynamicsapproach to generate many sample configurations of the compound andcomplexed target molecule, then calculates an interaction energy usingthe well-known AMBER force field (Cornell, et al Journal of the AmericanChemical Society 117:5179-97 1995) with corrections for desolvation andentropy of binding from the ensemble.

Use of this method yields binding energies highly correlated with thosefound experimentally. The absolute binding energies calculated with thismethod are reasonably accurate, and the variation of binding energies isapproximately linear with a slope of 1+/−0.5. Thus, the binding energiesof compounds interacting strongly with a given target will be lower thanabout −8 kcal/mol, while a binding energy of a good scaffold orunoptimized compound will be in the range of −3 to −7 kcal/mol.

Computer models, such as homology models (i.e., based on a known,experimentally derived structure) can be constructed using data from theco-crystal structures. A computer program such as Modeller (Accelrys,San Diego Calif.) may be used to assign the three dimensionalcoordinates to a protein sequence using an alignment of sequences and aset or sets of template coordinates. When the target molecule is aprotein or enzyme, preferred co-crystal structures for making homologymodels contain high sequence identity in the binding site of the proteinsequence being modeled, and the proteins will preferentially also bewithin the same class and/or fold family. Knowledge of conservedresidues in active sites of a protein class can be used to selecthomology models that accurately represent the binding site. Homologymodels can also be used to map structural information from a surrogateprotein where an apo or co-crystal structure exists to the targetprotein.

Virtual screening methods, such as docking, can also be used to predictthe binding configuration and affinity of scaffolds, compounds, and/orcombinatorial library members to homology models. Using this data, andcarrying out “virtual experiments” using computer software can savesubstantial resources and allow the person of ordinary skill to makedecisions about which compounds can be suitable scaffolds or ligands,without having to actually synthesize the ligand and performco-crystallization. Decisions thus can be made about which compoundsmerit actual synthesis and co-crystallization. An understanding of suchchemical interactions aids in the discovery and design of drugs thatinteract more advantageously with target proteins and/or are moreselective for one protein family member over others. Thus, applyingthese principles, compounds with superior properties can be discovered.

J. Ligand Design and Preparation

The design and preparation of ligands can be performed with or withoutstructural and/or co-crystallization data by considering the chemicalstructures in common between the active scaffolds of a set. In thisprocess structure-activity hypotheses can be formed and those chemicalstructures found to be present in a substantial number of the scaffolds,including those that bind with low affinity, can be presumed to havesome effect on the binding of the scaffold. This binding can be presumedto induce a desired biochemical effect when it occurs in a biologicalsystem (e.g., a treated mammal). New or modified scaffolds orcombinatorial libraries derived from scaffolds can be tested to disprovethe maximum number of binding and/or structure-activity hypotheses. Theremaining hypotheses can then be used to design ligands that achieve adesired binding and biochemical effect.

But in many cases it will be preferred to have co-crystallography datafor consideration of how to modify the scaffold to achieve the desiredbinding effect (e.g., binding at higher affinity or with higherselectivity). Using the case of proteins and enzymes, co-crystallographydata shows the binding pocket of the protein with the molecular scaffoldbound to the binding site, and it will be apparent that a modificationcan be made to a chemically tractable group on the scaffold. Forexample, a small volume of space at a protein binding site or pocketmight be filled by modifying the scaffold to include a small chemicalgroup that fills the volume. Filling the void volume can be expected toresult in a greater binding affinity, or the loss of undesirable bindingto another member of the protein family. Similarly, theco-crystallography data may show that deletion of a chemical group onthe scaffold may decrease a hindrance to binding and result in greaterbinding affinity or specificity.

Various software packages have implemented techniques which facilitatethe identification and characterization of interactions of potentialbinding sites from complex structure, or from an apo structure of atarget molecule, i.e. one without a compound bound (e.g. SiteID, TriposAssociates, St. Louis Mo. and SiteFinder, Chemical Computing Group,Montreal Canada, GRID, Molecular Discovery Ltd., London UK). Suchtechniques can be used with the coordinates of a complex between thescaffold of interest and a target molecule, or these data in conjunctionwith data for a suitably aligned or superimposed related targetmolecule, in order to evaluate changes to the scaffold that wouldenhance binding to the desired target molecule structure or structures.Molecular Interaction Field-computing techniques, such as thoseimplemented in the program GRID, result in energy data for particularpositive and negative binding interactions of different computationalchemical probes being mapped to the vertices of a matrix in thecoordinate space of the target molecule. These data can then be analyzedfor areas of substitution around the scaffold binding site which arepredicted to have a favorable interaction for a particular targetmolecule. Compatible chemical substitution on the scaffold e.g. amethyl, ethyl or phenyl group in a favorable interaction region computedfrom a hydrophobic probe, would be expected to result in an improvementin affinity of the scaffold. Conversely, a scaffold could be made moreselective for a particular target molecule by making such a substitutionin a region predicted to have an unfavorable hydrophobic interaction ina second, related undesirable target molecule.

It can be desirable to take advantage of the presence of a chargedchemical group located at the binding site or pocket of the protein. Forexample, a positively charged group can be complemented with anegatively charged group introduced on the molecular scaffold. This canbe expected to increase binding affinity or binding specificity, therebyresulting in a more desirable ligand. In many cases, regions of proteinbinding sites or pockets are known to vary from one family member toanother based on the amino acid differences in those regions. Chemicaladditions in such regions can result in the creation or elimination ofcertain interactions (e.g., hydrophobic, electrostatic, or entropic)that allow a compound to be more specific for one protein target overanother or to bind with greater affinity, thereby enabling one tosynthesize a compound with greater selectivity or affinity for aparticular family member. Additionally, certain regions can containamino acids that are known to be more flexible than others. This oftenoccurs in amino acids contained in loops connecting elements of thesecondary structure of the protein, such as alpha helices or betastrands. Additions of chemical moieties can also be directed to theseflexible regions in order to increase the likelihood of a specificinteraction occurring between the protein target of interest and thecompound. Virtual screening methods can also be conducted in silico toassess the effect of chemical additions, subtractions, modifications,and/or substitutions on compounds with respect to members of a proteinfamily or class.

The addition, subtraction, or modification of a chemical structure orsub-structure to a scaffold can be performed with any suitable chemicalmoiety. For example the following moieties, which are provided by way ofexample and are not intended to be limiting, can be utilized: hydrogen,alkyl, alkoxy, phenoxy, alkenyl, alkynyl, phenylalkyl, hydroxyalkyl,haloalkyl, aryl, arylalkyl, alkyloxy, alkylthio, alkenylthio, phenyl,phenylalkyl, phenylalkylthio, hydroxyalkyl-thio, alkylthiocarbbamylthio,cyclohexyl, pyridyl, piperidinyl, alkylamino, amino, nitro, mercapto,cyano, hydroxyl, a halogen atom, halomethyl, an oxygen atom (e.g.,forming a ketone or N-oxide) or a sulphur atom (e.g., forming a thiol,thione, di-alkylsulfoxide or sulfone) are all examples of moieties thatcan be utilized.

Additional examples of structures or sub-structures that may be utilizedare an aryl optionally substituted with one, two, or three substituentsindependently selected from the group consisting of alkyl, alkoxy,halogen, trihalomethyl, carboxylate, nitro, and ester moieties; an amineof formula —NX₂X₃, where X₂ and X₃ are independently selected from thegroup consisting of hydrogen, saturated or unsaturated alkyl, andhomocyclic or heterocyclic ring moieties; halogen or trihalomethyl; aketone of formula —COX₄, where X₄ is selected from the group consistingof alkyl and homocyclic or heterocyclic ring moieties; a carboxylic acidof formula —(X₅)_(n)COOH or ester of formula (X₆)_(n)COOX₇, where X₅,X₆, and X₇ and are independently selected from the group consisting ofalkyl and homocyclic or heterocyclic ring moieties and where n is 0 or1; an alcohol of formula (X₈)_(n)OH or an alkoxy moiety of formula—(X₈)_(n)OX₉, where X₈ and X₉ are independently selected from the groupconsisting of saturated or unsaturated alkyl and homocyclic orheterocyclic ring moieties, wherein said ring is optionally substitutedwith one or more substituents independently selected from the groupconsisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro,and ester and where n is 0 or 1; an amide of formula NHCOX₁₀, where X₁₀is selected from the group consisting of alkyl, hydroxyl, and homocyclicor heterocyclic ring moieties, wherein said ring is optionallysubstituted with one or more substituents independently selected fromthe group consisting of alkyl, alkoxy, halogen, trihalomethyl,carboxylate, nitro, and ester; SO₂, NX₁₁X₁₂, where X₁₁ and X₁₂ areselected from the group consisting of hydrogen, alkyl, and homocyclic orheterocyclic ring moieties; a homocyclic or heterocyclic ring moietyoptionally substituted with one, two, or three substituentsindependently selected from the group consisting of alkyl, alkoxy,halogen, trihalomethyl, carboxylate, nitro, and ester moieties; analdehyde of formula —COH; a sulfone of formula —SO₂X₁₃, where X₁₃ isselected from the group consisting of saturated or unsaturated alkyl andhomocyclic or heterocyclic ring moieties; and a nitro of formula —NO₂.

K. Identification of Binding Characteristics of Binding Compounds

It can also be beneficial in selecting compounds for testing to firstidentify binding characteristics that a ligand should advantageouslypossess. This can be accomplished by analyzing the interactions that aplurality of different binding compounds have with a particular target,e.g., interactions with one or more conserved residues in the bindingsite. These interactions are identified by considering the nature of theinteracting moieties. In this way, atoms or groups that can participatein hydrogen bonding, polar interactions, charge-charge interactions, andthe like are identified based on known structural and electronicfactors.

L. Identification of Energetically Allowed Sites for Attachment

In addition to the identification and development of ligands,determination of the orientation of a molecular scaffold or otherbinding compound in a binding site allows identification ofenergetically allowed sites for attachment of the binding molecule toanother component. For such sites, any free energy change associatedwith the presence of the attached component should not destablize thebinding of the compound to the target to an extent that will disrupt thebinding. Preferably, the binding energy with the attachment should be atleast 4 kcal/mol., more preferably at least 6, 8, 10, 12, 15, or 20kcal/mol. Preferably, the presence of the attachment at the particularsite reduces binding energy by no more than 3, 4, 5, 8, 10, 12, or 15kcal/mol.

In many cases, suitable attachment sites will be those that are exposedto solvent when the binding compound is bound in the binding site. Insome cases, attachment sites can be used that will result in smalldisplacements of a portion of the enzyme without an excessive energeticcost. Exposed sites can be identified in various ways. For example,exposed sites can be identified using a graphic display or 3-dimensionalmodel. In a graphic display, such as a computer display, an image of acompound bound in a binding site can be visually inspected to revealatoms or groups on the compound that are exposed to solvent and orientedsuch that attachment at such atom or group would not preclude binding ofthe enzyme and binding compound. Energetic costs of attachment can becalculated based on changes or distortions that would be caused by theattachment as well as entropic changes.

Many different types of components can be attached. Persons with skillare familiar with the chemistries used for various attachments. Examplesof components that can be attached include, without limitation: solidphase components such as beads, plates, chips, and wells; a direct orindirect label; a linker, which may be a traceless linker; among others.Such linkers can themselves be attached to other components, e.g., tosolid phase media, labels, and/or binding moieties.

The binding energy of a compound and the effects on binding energy forattaching the molecule to another component can be calculatedapproximately by manual calculation, or by using any of a variety ofavailable computational virtual assay techniques, such as docking ormolecular dynamics simulations. A virtual library of compounds derivedfrom the attachment of components to a particular scaffold can beassembled using a variety of software programs (such as Afferent, MDLInformation Systems, San Leandro, Calif. or CombiLibMaker, TriposAssociates, St. Louis, Mo.). This virtual library can be assignedappropriate three dimensional coordinates using software programs (suchas Concord, Tripos Associates, St. Louis, Mo. or Omega, OpeneyeScientific Software, Santa Fe, N. Mex.). These structures may then besubmitted to the appropriate computational technique for evaluation ofbinding energy to a particular target molecule. This information can beused for purposes of prioritizing compounds for synthesis, for selectinga subset of chemically tractable compounds for synthesis, and forproviding data to correlate with the experimentally determined bindingenergies for the synthesized compounds.

The crystallographic determination of the orientation of the scaffold inthe binding site specifically enables more productive methods ofassessing the likelihood of the attachment of a particular componentresulting in an improvement in binding energy. Such an example is shownfor a docking-based strategy in Haque et al Journal of MedicinalChemistry 42:1428-40, 1999, wherein an “Anchor and Grow” technique whichrelied on a crystallographically determined fragment of a largermolecule, potent and selective inhibitors were rapidly created. The useof a crystallographically characterized small molecule fragment inguiding the selection of productive compounds for synthesis has alsobeen demonstrated in Boehm et al, Journal of Medicinal Chemistry43:2664-74, 2000. An illustration of the use of crystallographic dataand molecular dynamics simulations in the prospective assessment ofinhibitor binding energies can be found in Pearlman and Charifson,Journal of Medicinal Chemistry 44, 3417-23, 2001. Another importantclass of techniques which rely on a well defined structural startingpoint for computational design is the combinatorial growth algorithmbased systems, such as the GrowMol program (Bohacek and McMartin,Journal of the American Chemical Society 116:5560-71, 1994. Thesetechniques have been used to enable the rapid computational evolution ofvirtual inhibitor computed binding energies, and directly led to morepotent synthesized compounds whose binding mode was validatedcrystallographically (see Organic Letters (2001) 3(15):2309-2312).

(1) Linkers

Linkers suitable for use in the invention can be of many differenttypes. Linkers can be selected for particular applications based onfactors such as linker chemistry compatible for attachment to a bindingcompound and to another component utilized in the particularapplication. Additional factors can include, without limitation, linkerlength, linker stability, and ability to remove the linker at anappropriate time. Exemplary linkers include, but are not limited to,hexyl, hexatrienyl, ethylene glycol, and peptide linkers. Tracelesslinkers can also be used, e.g., as described in Plunkett, M. J., andEllman, J. A., 1995, J. Org. Chem., 60:6006.

Typical functional groups, that are utilized to link bindingcompound(s), include, but not limited to, carboxylic acid, amine,hydroxyl, and thiol. (Examples can be found in Solid-supportedcombinatorial and parallel synthesis of small molecular weight compoundlibraries; Tetrahedron organic chemistry series Vol. 17; Pergamon, 1998;p 85).

(2) Labels

As indicated above, labels can also be attached to a binding compound orto a linker attached to a binding compound. Such attachment may bedirect (attached directly to the binding compound) or indirect (attachedto a component that is directly or indirectly attached to the bindingcompound). Such labels allow detection of the compound either directlyor indirectly. Attachment of labels can be performed using conventionalchemistries. Labels can include, for example, fluorescent labels,radiolabels, light scattering particles, light absorbent particles,magnetic particles, enzymes, and specific binding agents (e.g., biotinor an antibody target moiety).

(3) Solid Phase Media

Additional examples of components that can be attached directly orindirectly to a binding compound include various solid phase media.Similar to attachment of linkers and labels, attachment to solid phasemedia can be performed using conventional chemistries. Such solid phasemedia can include, for example, small components such as beads,nanoparticles, and fibers (e.g., in suspension or in a gel orchromatographic matrix). Likewise, solid phase media can include largerobjects such as plates, chips, slides, and tubes. In many cases, thebinding compound will be attached in only a portion of such an objects,e.g., in a spot or other local element on a generally flat surface or ina well or portion of a well.

IV. Administration

The methods and compounds will typically be used in therapy for humanpatients. However, they may also be used to treat similar or identicaldiseases in other vertebrates, e.g., mammals such as other primates,sports animals, bovines, equines, porcines, ovines, and pets such asdogs and cats.

Suitable dosage forms, in part, depend upon the use or the route ofadministration, for example, oral, transdermal, transmucosal, or byinjection (parenteral). Such dosage forms should allow the compound toreach target cells. Other factors are well known in the art, and includeconsiderations such as toxicity and dosage forms that retard thecompound or composition from exerting its effects. Techniques andformulations generally may be found in Remington's PharmaceuticalSciences, 18^(th) ed., Mack Publishing Co., Easton, Pa., 1990 (herebyincorporated by reference herein).

Compounds can be formulated as pharmaceutically acceptable salts.Pharmaceutically acceptable salts are non-toxic salts in the amounts andconcentrations at which they are administered. The preparation of suchsalts can facilitate the pharmacological use by altering the physicalcharacteristics of a compound without preventing it from exerting itsphysiological effect. Useful alterations in physical properties includelowering the melting point to facilitate transmucosal administration andincreasing the solubility to facilitate administering higherconcentrations of the drug.

Pharmaceutically acceptable salts include acid addition salts such asthose containing sulfate, chloride, hydrochloride, fumarate, maleate,phosphate, sulfamate, acetate, citrate, lactate, tartrate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptablesalts can be obtained from acids such as hydrochloric acid, maleic acid,sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid,lactic acid, tartaric acid, malonic acid, methanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,cyclohexylsulfamic acid, fumaric acid, and quinic acid.

Pharmaceutically acceptable salts also include basic addition salts suchas those containing benzathine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, procaine, aluminum, calcium, lithium,magnesium, potassium, sodium, ammonium, alkylamine, and zinc, whenacidic functional groups, such as carboxylic acid or phenol are present.For example, see Remington's Pharmaceutical Sciences, 19^(th) ed., MackPublishing Co., Easton, Pa., Vol. 2, p. 1457, 1995. Such salts can beprepared using the appropriate corresponding bases.

Pharmaceutically acceptable salts can be prepared by standardtechniques. For example, the free-base form of a compound is dissolvedin a suitable solvent, such as an aqueous or aqueous-alcohol in solutioncontaining the appropriate acid and then isolated by evaporating thesolution. In another example, a salt is prepared by reacting the freebase and acid in an organic solvent.

The pharmaceutically acceptable salt of the different compounds may bepresent as a complex. Examples of complexes include 8-chlorotheophyllinecomplex (analogous to, e.g., dimenhydrinate: diphenhydramine8-chlorotheophylline (1:1) complex; Dramamine) and various cyclodextrininclusion complexes.

Carriers or excipients can be used to produce pharmaceuticalcompositions. The carriers or excipients can be chosen to facilitateadministration of the compound. Examples of carriers include calciumcarbonate, calcium phosphate, various sugars such as lactose, glucose,or sucrose, or types of starch, cellulose derivatives, gelatin,vegetable oils, polyethylene glycols and physiologically compatiblesolvents. Examples of physiologically compatible solvents includesterile solutions of water for injection (WFI), saline solution, anddextrose.

The compounds can be administered by different routes includingintravenous, intraperitoneal, subcutaneous, intramuscular, oral,transmucosal, rectal, or transdermal. Oral administration is preferred.For oral administration, for example, the compounds can be formulatedinto conventional oral dosage forms such as capsules, tablets, andliquid preparations such as syrups, elixirs, and concentrated drops.

Pharmaceutical preparations for oral use can be obtained, for example,by combining the active compounds with solid excipients, optionallygrinding a resulting mixture, and processing the mixture of granules,after adding suitable auxiliaries, if desired, to obtain tablets ordragee cores. Suitable excipients are, in particular, fillers such assugars, including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations, for example, maize starch, wheat starch, rice starch,potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC),and/or polyvinylpyrrolidone (PVP: povidone). If desired, disintegratingagents may be added, such as the cross-linked polyvinylpyrrolidone,agar, or alginic acid, or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally contain,for example, gum arabic, talc, poly-vinylpyrrolidone, carbopol gel,polyethylene glycol (PEG), and/or titanium dioxide, lacquer solutions,and suitable organic solvents or solvent mixtures. Dye-stuffs orpigments may be added to the tablets or dragee coatings foridentification or to characterize different combinations of activecompound doses.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin (“gelcaps”), as well as soft, sealed capsulesmade of gelatin, and a plasticizer, such as glycerol or sorbitol. Thepush-fit capsules can contain the active ingredients in admixture withfiller such as lactose, binders such as starches, and/or lubricants suchas talc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols (PEGs). In addition, stabilizers may be added.

Alternatively, injection (parenteral administration) may be used, e.g.,intramuscular, intravenous, intraperitoneal, and/or subcutaneous. Forinjection, the compounds of the invention are formulated in sterileliquid solutions, preferably in physiologically compatible buffers orsolutions, such as saline solution, Hank's solution, or Ringer'ssolution. In addition, the compounds may be formulated in solid form andredissolved or suspended immediately prior to use. Lyophilized forms canalso be produced.

Administration can also be by transmucosal or transdermal means. Fortransmucosal or transdermal administration, penetrants appropriate tothe barrier to be permeated are used in the formulation. Such penetrantsare generally known in the art, and include, for example, fortransmucosal administration, bile salts and fusidic acid derivatives. Inaddition, detergents may be used to facilitate permeation. Transmucosaladministration, for example, may be through nasal sprays orsuppositories (rectal or vaginal).

The amounts of various compound to be administered can be determined bystandard procedures taking into account factors such as the compoundIC₅₀, the biological half-life of the compound, the age, size, andweight of the patient, and the disorder associated with the patient. Theimportance of these and other factors are well known to those ofordinary skill in the art. Generally, a dose will be between about 0.01and 50 mg/kg, preferably 0.1 and 20 mg/kg of the patient being treated.Multiple doses may be used.

V. Synthesis of Compounds of Formula I

Compounds with the chemical structure of Formula I can be prepared in anumber of different synthetic routes, including, for example, thesynthetic schemes described herein for groups of compounds withinFormula I. Additional synthetic routes can be utilized by one skilled inchemical synthesis.

Certain of the syntheses can utilize key intermediate II in thesynthesis. Key intermediate II can be prepared as follows:

Synthesis of Key Intermediate II

One synthetic route for Intermediate II compounds is shown below. Inthese compounds, Y and Z (as well as U, V, and W) can be C as in indole,or can be other heteroatoms as specified for Formula I, and R³, R⁴, andR⁵ are as specified for Formula I or a sub-generic description withinFormula I. In synthetic Scheme Ia and other synthetic schemes describedherein for groups of compounds, it should be understood that genericformulas in the schemes (e.g., Formula III in Scheme 1a) describe a setof compounds, but are referenced in the text description of thesynthesis in the singular.

Step 1-Preparation of Compound of Formula IV

Compound IV was prepared by reacting commercially available aldehyde IIIwith an activated phosphonate ester in an inert solvent (e.g.tetrahydrofuran) under reflux conditions, typically for 16-24 h, asdescribed by Garuti et al in Arch. Pharm, 1988, 321, 377-83). CompoundIII, in turn, can be prepared by reacting compound V under Vilsmeier(POCl₃ and DMF) conditions as described by in March's Advanced OrganicChemstry, 5^(th) Edition, p. 715.

Step 2-Preparation of Intermediate II

Key intermediate II was prepared by the reduction of IV in an inertsolvent (i.e. tetrahydrofuran) by catalytic hydrogenation (typically 10%palladium on activated carbon and atmospheric hydrogen) as described byGaruti et al in Arch. Pharm, 1988, 321, 377-83).

Key Intermediate II compounds can also be prepared in accordance withScheme 1b as shown below.

Step 1-Preparation of Formula VI

Compound VI was prepared conventionally by a reacting commerciallyavailable compound of formula V with an N,N-dialkyl amine hydrochloridein a polar solvent (e.g. i-Propanol), in the presence of formaldehydeand heated, typically near 90° C., typically for 24 h, as described bySnyder et al, JACS, 73, 970.

Step 2-Preparation of Formula VII

Compound of formula VII was prepared by heating compound VI with diethylmalonate and a catalytic amount of sodium metal, typically at 120° C. asdescribed by Robinson et. al, JACS, 78, 1247, followed by flashchromatography purification.

Step 3-Preparation of Formula Ia

Compound of formula Ia was prepared by hydrolyzing compound VII usingaqueous base (e.g. NaOH) followed by the decarboxylation under refluxconditions (JACS, 78, 1247).

Step 4-Preparation of Intermediate II

Intermediate II was prepared by Fisher esterification of compound Iawith alcohol (e.g. Methanol) and catalytic amount of an acid (e.g. HCl)under reflux, typically for 16-24 h.

Step 1-Preparation of Formula VIII

Compound VIII can be prepared by a reacting commercially available of acompound of formula V with bromine in an inert solvent (e.g. DMF)(Bocchi and Palla; Synthesis, 1982, p 1096).

Step 2-Preparation of Formula IV

Compound IV can be prepared by a reacting compound of formula VIII withmethacrylate under Heck coupling conditions as described by Sznaidmanet. al, in Bioorg. Med. Chem. Lett., 13, 2003, 1517.

Step 3-Preparation of Intermediate II

Key intermediate II was prepared by the reduction of IV in an inertsolvent (i.e. tetrahydrofuran) by catalytic hydrogenation (typically 10%palladium on activated carbon and atmospheric hydrogen) as described byAaruti et. al in Arch. Pharm, 321, 1988, 377-83.

Synthesis of Compound Ia

Compounds of Formula Ia can be prepared by hydrolysis of KeyIntermediate II as shown in Scheme II.

Compound of formula Ia was prepared by the hydrolysis of keyintermediate of formula II with aqueous base (e.g. aq. NaOH), typicallyfor 6-15 h and isolating the product by conventional methods (e.g.aqueous work up and purification by chromatography) Jerry March inMarch's Advanced Organic Chemstry, 5^(th) Edition, p. 715.

Synthesis of Compound Ib

Compounds of Formula Ib, in which the indole ring is substituted at the3-position (or corresponding position of the other bi-cyclic rings ofFormula I), can be prepared according to Scheme 3.

Step 1-Preparation of Compound of Formula IXa

Compound of formula IXa was prepared by treating intermediate of formulaII with a base (e.g. sodium hydride) in an inert solventN,N-Dimethylformamide, followed by the addition of R²W, where “W” is aleaving group (e.g. chloro, bromo), and stirring at RT, typically for 16to 24 h (Jerry March in March's Advanced Organic Chemstry, 5th Edition,p. 576). The product was obtained by column chromatography (e.g. silicagel) after workup using conventional methods.

Step 2-Preparation of Compound of Formula Ib

Compound of formula Ib was prepared by the hydrolysis of compound offormula V with aqueous base (e.g. aq. NaOH), typically for 6-15 h andisolating the product by conventional methods (e.g. aqueous work up andpurification by chromatography).

Synthesis of Compound Ic

Compounds of Formula Ic, in which R² is R¹⁰R¹¹NCZ, can be preparedaccording to Scheme 4.

Step 1-Preparation of Compound of Formula IXb

Compound of formula IXb was prepared by treating intermediate of formulaII with a base (e.g. sodium hydride) in an inert solvent (DMF) followedby the addition of R¹⁶NCZ, where “Z” is oxygen or sulfur, and stirringat RT, typically for 16 to 24 h (Jerry March in March's Advanced OrganicChemstry, 5^(th) Edition, p 1191). The product was obtained by columnchromatography (e.g. silica gel) after workup using conventionalmethods.

Compound of formula IXb can also be prepared by treating intermediate offormula II with R¹⁶NCZ, where “Z” is oxygen or sulfur, in an inertsolvent (THF) followed by the addition of catalytic amount of DMAP(N,N,-dimethylaminopyridine) and stirring at RT, typically for 16 to 24h. The product can be obtained by column chromatography (e.g. silicagel) after workup using conventional methods.

Step 2-Preparation of Compound of Formula Ic

Compound of formula Ic was prepared by the hydrolysis of compound offormula IXb with aqueous base (e.g. aq. NaOH), typically for 6-15 h andisolating the product by conventional methods (e.g. aqueous work up andpurification by chromatography).

In compound of formula Ic, substituent R² would then be R¹⁰R¹¹NCZ.

Synthesis of Compound Id

Compounds of Formula Id can be prepared according to Scheme 5a.

Step 1-Preparation of Compound of Formula IXd

Compound of formula IXd was prepared from compound of formula IXc byreacting it with aryl boronic acids under Suzuki reaction conditions(March's Advanced Organic Chemistry, 5^(th) Edition, p 8) and heatingthe reaction mixture, typically 90° C., for 24 and isolating the productby conventional methods (e.g. aqueous work up and purification bychromatography).

Compound of formula IXc was in turn prepared from commercially availablecompound of formula V, where “R⁴” is bromine, using the synthetic stepsdescribed in Scheme 1b, followed by the reaction with “R¹⁶W” asdescribed in step 1 of synthetic Scheme 3, where “R⁴” is bromine.

Step 2-Preparation of Compound of Formula Id

Compound of formula Id was prepared by the hydrolysis of compound offormula IXd with aqueous base (e.g. aq. NaOH), typically for 6-15 h andisolating the product by conventional methods (e.g. aqueous work up andpurification by chromatography).

Step 1-Preparation of Compound of Formula V

Compound of formula V was prepared from commercially available compoundof formula Va by reacting it with aryl boronic acids under Kumadareaction conditions as described by Hayashi et. al, JACS, 106 (1984),158-163, and heating the reaction mixture, typically 90° C., for 24 andisolating the product by conventional methods (e.g. aqueous work up andpurification by chromatography).

Step 2-Preparation of Formula VI

Compound VI was prepared conventionally by a reacting commerciallyavailable compound of formula V with an N,N-dialkyl amine hydrochloridein a polar solvent (e.g. i-Propanol), in the presence of formaldehydeand heated, typically near 90° C., typically for 24 h, as describedpreviously for compound VI.

Step 3-Preparation of Formula VII

Compound of formula VII was prepared by heating compound V1 with diethylmalonate and a catalytic amount of sodium metal, typically at 120° C. asdescribed previously, followed by flash chromatography purification.

Step 4-Preparation of Formula Ia

Compound of formula Ia was prepared by hydrolyzing compound VII usingaqueous base (e.g. NaOH) followed by the decarboxylation under refluxconditions as described previously.

Step 5-Preparation of Intermediate II

Intermediate II was prepared by Fisher esterification of compound Iawith alcohol (e.g. Methanol) and catalytic amount of an acid (e.g. HCl)under reflux, typically for 16-24 h.

Step 6-Preparation of Compound of Formula IXa

Compound of formula IXa was prepared by treating intermediate of formulaII with a base (e.g. sodium hydride, NaH) in an inert solvent (DMF)followed by the addition of “R²W”, where “W” is a leaving group (e.g.chloro, bromo), and stirring at RT, typically for 16 to 24 h. Theproduct was obtained by column chromatography (e.g. silica gel) afterworkup using conventional methods.

Step 7-Preparation of Compound of Formula Ib

Compound of formula Ib was prepared by the hydrolysis of compound offormula IXa with aqueous base (e.g. aq. NaOH), typically for 6-15 h andisolating the product by conventional methods (e.g. aqueous work up andpurification by chromatography).

Synthesis of Compound X

Step-1 Preparation of Intermediate XI

Compound XI was prepared from the compound V reacting withγ-butyrolatone in an inert solvent with potassium hydroxide under refluxconditions, usually 4 to 24 hours, as described by Fritz et al, (J. Org.Chem., 1963, 28, 1384-1385).

Step 2-Preparation of Intermediate XII

Compound XII was prepared by the carboxylic acid XI reacting in either acatalytic amount of sulfuric acid in methanol under reflux conditions,or activated methylene moiety such as diazomethane.

Step 3-Preparation of Intermediate XIII

Compound XIII was prepared by treating intermediate of formula XII witha base (e.g. sodium hydride) in an inert solvent (DMF) followed by theaddition of R²W, where “W” is a leaving group (e.g. chloro, bromo), andstirring at RT, typically for 16 to 24 h (Jerry March in March'sAdvanced Organic Chemstry, 5^(th) Edition, p. 576). The product wasobtained by column chromatography (e.g. silica gel) after workup usingconventional methods.

Step 4-Preparation of Intermediate X

Compound of formula X was prepared by the hydrolysis of compound offormula XIII with aqueous base (e.g. aq. NaOH), typically for 6-15 h andisolating the product by conventional methods (e.g. aqueous work up andpurification by chromatography).

Synthesis of Compound XIV

Step 1: Preparation of Intermediate XV

Compound XV can be prepared from the corresponding aldehyde III reactingwith a reducting agent such as sodium borohydride in an inert solvent(e.g. tetrahydrofuran).

Step 2: Preparation of Intermediate XVI

Compound XVI can be prepared by reacting the methanol XV with silylketene acetal in presence of a catalyst such as magnesium triflimide orperchlorate at ambient temperature for 1-2 hours as described by Griecoet al in Tetrandron Letts (1997, 38, 2645-2648).

Step 3: Preparation of Intermediate XVII

Compound XVII was prepared by treating intermediate of formula XVI witha base (e.g. sodium hydride) in an inert solvent (DMF) followed by theaddition of R²W, where “W” is a leaving group (e.g. chloro, bromo), andstirring at RT, typically for 16 to 24 h (Jerry March in March'sAdvanced Organic Chemstry, 5^(th) Edition, p. 576). The product wasobtained by column chromatography (e.g. silica gel) after workup usingconventional methods.

Step 4 Preparation of Intermediate XIV

Compound of formula XIV was prepared by the hydrolysis of compound offormula XVII with aqueous base (e.g. aq. NaOH), typically for 6-15 h andisolating the product by conventional methods (e.g. aqueous work up andpurification by chromatography).

Using the synthetic schemes described above, a set of exemplary compoundwas prepared. Those compounds include those listed below, which are alsolisted in Table 1 along with the chemical structures, along withadditional exemplary compounds.

-   3-[5-Methoxy-1-(4-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic    acid,-   3-[5-ethyl-1-(4-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic    acid,-   Indazole-3-propionic acid,-   5-isopropoxy-3-(1-Benzene-sulfonyl-indol-3-yl)-propionic acid,-   Indole-3-propionic acid,-   3-(1-Benzenesulfonyl-5-methoxy-1H-indol-3-yl)-propionic acid,-   3-[5-Methoxy-1-(3-methoxy-benzyl)-1H-indol-3-yl]-propionic acid,-   3-[1-(3-Chloro-benzyl)-5-methoxy-1H-indol-3-yl]-propionic acid,-   3-[1-(4-Fluoro-benzyl)-5-methoxy-1H-indol-3-yl]-propionic acid,-   3-[1-(4-Chloro-benzyl)-5-methoxy-1H-indol-3-yl]-propionic acid,-   3-[5-Methoxy-1-(2-methoxy-benzyl)-1H-indol-3-yl]-propionic acid,-   3-[5-Methoxy-1-(2-trifluoromethoxy-benzyl)-1H-indol-3-yl]-propionic    acid,-   3-[5-Methoxy-1-(3-trifluoromethoxy-benzyl)-1H-indol-3-yl]-propionic    acid,-   3-(1-Ethylthiocarbamoyl-5-methoxy-1H-indol-3-yl)-propionic acid,-   3-[5-Methoxy-1-(toluene-4-sulfonyl)-1H-indol-3-yl]-propionic acid,-   3-(1-Benzenesulfonyl-1H-indazol-3-yl)-propionic acid,-   3-[1-(4-Isopropyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic    acid methyl ester,-   3-[1-(4-Isopropyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic    acid,-   3-[1-(4-Butoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic    acid methyl ester,-   3-[1-(4-Butoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic    acid,-   3-[5-Methoxy-1-(4-trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic    acid methyl ester,-   3-[5-Methoxy-1-(4-trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic    acid,-   3-[5-Methoxy-1-(4-phenoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic    acid methyl ester,-   3-[5-Methoxy-1-(4-phenoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic    acid,-   3-[1-(4-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic    acid methyl ester,-   3-[1-(4-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic    acid,-   3-[1-(4-Cyano-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic    acid methyl ester,-   3-[1-(4-Cyano-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic    acid,-   3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic    acid methyl ester,-   3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic    acid,-   3-[5-Methoxy-1-(4-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]-propionic    acid methyl ester,-   3-[5-Methoxy-1-(4-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]-propionic    acid,-   3-[1-(4-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic    acid methyl ester,-   3-[1-(4-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic    acid,-   3-[5-Methoxy-1-(3-phenoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic    acid methyl ester,-   3-[5-Methoxy-1-(3-phenoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic    acid,-   3-[1-(3-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic    acid methyl ester,-   3-[1-(3-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic    acid,-   3-[5-Methoxy-1-(toluene-3-sulfonyl)-1H-indol-3-yl]-propionic acid    methyl ester,-   3-[5-Methoxy-1-(toluene-3-sulfonyl)-1H-indol-3-yl]-propionic acid,-   3-[1-(3-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic    acid methyl ester,-   3-[1-(3-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic    acid,-   3-[5-Methoxy-1-(3-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic    acid methyl ester,-   3-[5-Methoxy-1-(3-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic    acid,-   3-[5-Methoxy-1-(3-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]-propionic    acid methyl ester,-   3-[5-Methoxy-1-(3-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]-propionic    acid,-   3-(1-Benzyl-5-methoxy-1H-indol-3-yl)-propionic acid methyl ester,-   3-(1-Benzyl-5-methoxy-1H-indol-3-yl)-propionic acid,-   3-[5-Methoxy-1-(thiophene-2-sulfonyl)-1H-indol-3-yl]-propionic acid    methyl ester,-   3-[5-Methoxy-1-(thiophene-2-sulfonyl)-1H-indol-3-yl]-propionic acid,-   3-(5-Methoxy-1-phenylthiocarbamoyl-1H-indol-3-yl)-propionic acid    methyl ester,-   3-(5-Methoxy-1-phenylthiocarbamoyl-1H-indol-3-yl)-propionic acid,-   3-[1-(4-Butyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic    acid methyl ester,-   3-[1-(4-Butyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic    acid,-   3-[5-Methoxy-1-(3-trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic    acid methyl ester,-   3-[5-Methoxy-1-(3-trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic    acid,-   3-(1-Benzoyl-5-methoxy-1H-indol-3-yl)-propionic acid methyl ester,-   3-(1-Benzoyl-5-methoxy-1H-indol-3-yl)-propionic acid,-   3-(1-Benzenesulfonyl-5-ethoxy-1H-indol-3-yl)-propionic acid,-   3-[1-(4-Isopropoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic    acid,-   3-(5-Methoxy-1-phenylcarbamoyl-1H-indol-3-yl)-propionic acid methyl    ester,-   3-(5-Methoxy-1-phenylcarbamoyl-1H-indol-3-yl)-propionic acid,-   3-[1-(4-Ethyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic    acid,-   3-(5-bromo-1H-indol-3-yl)-propionic acid,    3-(5-Bromo-1H-indol-3-yl)-propionic acid methyl ester,-   3-(1-Benzenesulfonyl-5-bromo-1H-indol-3-yl)-propionic acid methyl    ester,-   3-(1-Benzenesulfonyl-5-bromo-1H-indol-3-yl)-propionic acid methyl    ester,-   3-(Benzenesulfonyl-5-thiophen-3-yl-1H-indol-3-yl)-propionic acid    methyl ester,-   3-(Benzenesulfonyl-5-thiophen-3-yl-1H-indol-3-yl)-propionic acid,-   3-(1-Benzenesulfonyl-5-pheyl-1H-indol-3-yl) propionic acid methyl    ester,-   3-(1-Benzenesulfonyl-5-pheyl-1H-indol-3-yl) propionic acid,-   Preparation of 3-(1H-Pyrrolo[2,3-b]pyridine-3-yl)-propionic acid,-   3-(5-Methoxy-1H-Indol-3-yl)-propionic acid,-   3-(1-Benzenesulfonyl-1H-indol-3-yl)-propionic acid,-   3-(1-Benzenesulfonyl-5-methoxy-1H-indol-3-yl)-propionic acid methyl    ester,-   3-[5-Methoxy-1-(thiophene-3-sulfonyl)-1H-indol-3-yl]-propionic acid,-   (1-Benzenesulfonyl-5-methoxy-1H-indol-3-yl)-acetic acid.

EXAMPLES Example 1 Bio-Chemical Screening

The homogenous Alpha screen assay was used in the agonist mode todetermine the ligand dependent interaction of the PPARs (α,δ,γ) with theco-activator peptides (SRC or DRIP205). Briefly 15 ul of the reactionmix (50 mM Tris pH 7.5, 50 mM Kcl, 0.05% Tween 20, 1 mM DTT, 0.1% BSAand 10 nM-200 nMPPAR and 10 nM-200 nM co-activator peptide) was added tothe test compound (1 ul compound in DMSO) and preincubated for 1-6 hr.Next, 5 ul of the Alpha screen beads were added. The reactions wereincubated for 2 hrs before taking the reading in the Fusion alphainstrument. In the antagonist mode compounds were assayed for inhibitionof the co-activator binding signal caused by the control agonists foreach receptor.

The controls agonists used were WY-14643 (PPAR(α), farglitazar (PPAR (γ)and bezafibrate (PPAR (δ).

Using the assay above, compounds from Table 1 were analyzed foractivity. Results for exemplary compounds are shown in Table 2. The datareported in Table 2 was generated via the alpha screen assay andexpressed in μMol/L. The data points from the Fusion alpha instrumentwere transferred to Assay Explorer® (MDL) to generate a curve andcalculate the inflection point of the curve as EC₅₀.

Among those compounds, several have notable pan-activity at lowmicromolar or even sub-micromolar levels, for example, compounds 29, 43,and 53. In contrast, compound 6 is selective for PPARγ, with activity onPPARγ of approximately 8 micromolar and activity on PPARα and δ of atleast 200 micromolar.

Example 2 Co-Transfection Assay

293T cells were transfected for 4-5 hr in serum free DMEM media usingcell fectin reagent. Each well was transfected with 1 μg each of thereporter plasmid (pFR-Luc from stratagene) and PPAR constructs(Gal4-PPAR-LBD). After 24 hrs of recovery in serum medium the cells weretreated with compounds for 48 hrs then assayed for luciferase activityusing luciferase reporter gene assay kit (Roche).

This assay serves to confirm the observed biochemical activity on themodulation of intended target molecule(s) at the cellular level.

Example 3 Synthesis of3-[5-methoxy-1-(4-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid1

Indole-3-propionic acid 1 was synthesized from the commerciallyavailable 5-methoxyindole-3-carboxaldehye in four steps as shown inScheme 7.

Step 1-Preparation of 3-(5-Methoxy-1H-indol-3-yl)-acrylic acid methylester 3

To a cold solution (ice bath) of methyl phosphonoacetate (13.74 g, 0.065mol) in tetrahydrofuran (120 mL) under nitrogen, was added sodiumhydride (2.6 g, 0.065 mol, 60%) in one portion, and stirred untilhydrogen evolution ceased. A solution of commercially available5-Methoxyindole-3-carboxyaldehyde 2 (5.2 g, 0.029 mol) intetrahydrofuran (80 mL) was added, over a period of 60 minutes, to thephosphonate solution. The reaction mixture was heated to 55° C. for 24 hafter which the mixture was diluted with dichloromethane (DCM, 500 mL)and washed with water (200 mL; 3×). The organic layer was washed oncewith brine, dried over anhydrous sodium sulfate, and evaporated underreduced pressure to give yellow-tinted oil and purified by filteringthrough a silica plug. The filtrate was evaporated to afford 3 as an offwhite solid (6.2 g; 78% yield; M+1=232.0).

Step 2-Preparation of 3-(5-Methoxy-1H-indol-3-yl)-propionic acid methylester 4:

To a solution of 3-(5-Methoxy-1H-indol-3-yl)-acrylic acid methyl ester 3(3 g; 0.013 mol) in tetrahydrofuran (THF, 70 mL) was added palladium onactivated carbon (10%; 0.72 g). The solution was deoxygenated undervacuum and hydrogen was introduced to the reaction flask from a balloonfilled with hydrogen. The process was repeated three times and thereaction mixture was stirred for 16 h at room temperature. The mixturewas filtered through celite and the filtrate was evaporated underreduced pressure to yield ester 4 as a while solid (2.78 g; 92% yield;M+1=234.0).

Step 3-Preparation of3-[5-Methoxy-1-(4-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acidmethyl ester 5:

To a cooled solution (0° C.) of indole-3-propionic acid methyl ester 4(0.797 g, 3.42 mmol) in DMF (20 mL) was added sodium hydride (60%; 0.25g; 0.0625 mol) was added in one portion and stirred for 30 min followedby the addition of 4-methoxybenzenesulfonyl chloride (1.3 g; 6.31 mmol).The reaction was allowed to warm up to room temperature and stirred for16 h, subjected to aqueous work up, and product was extracted with ethylacetate. The ethyl acetate layer was washed with brine, dried overanhydrous sodium sulfate, evaporated under reduced pressure, andpurified by flash-chromatography (silica gel; 80% n-hexane-20% ethylacetate) to afford the ester 5 as a white solid (0.83 g; 61% yield;M+1=404.1).

Step 4-Preparation of3-[5-Methoxy-1-(4-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid1

To a solution of the methyl ester 5 (830 mg, 2.06 mmol) intetrahydrofuran (15 mL) was added an aqueous solution of potassiumhydroxide (5 mL of 1M) and stirred at room temperature for 5 h. The acid1 was isolated by neutralizing the reaction mixture by aqueoushydrochloric acid, extracting the product with ethyl acetate, dryingover anhydrous magnesium sulfate, evaporating under reduced pressure,and purifying using flash chromatography with 5% methanol indichloromethane to afford a white solid (697.5 mg, 91%; M−1=373.1).

Example 4 Synthesis of3-[5-ethyl-1-(4-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid 6

Indole-3-propionic acid 6 was synthesized from the commerciallyavailable 5-bromo-indole 7 in eight steps as shown in Scheme 8.

Step 1-Preparation of 5-Bromo-1-triisopropylsilanyl-1H-indole 8

5-Bromoindole (2.5 g, 12.75 mmol) was dissolved in tetrahydrofuran (THF;50 mL) and cooled to 0° C. and Sodium Hydride NaH (920 mg, 23 mmol, 60%)was added in portions. The mixture was allowed to warm to RT withstirring for 1 hour. The reaction mixture was again cooled to 0° C. andtriisopropylsilyl chloride (TIPSCl; 2.78 mL, 13.1 mmol) was addeddropwise. The mixture was allowed to warm to room temperature and wasstirred overnight. The mixture was washed with 2.0 N H₃PO₄, and theorganic layer was dried over MgSO₄, filtered and evaporated. The residuewas purified by flash silica chromatography (100% Hexanes) to givecompound 8 as an oil (4.3 g; 96% yield; M+1=353.4)

Step 2-Preparation of 5-Ethyl-1-triisopropylsilanyl-1H-indole 9

The 1-triisopropyl-5-bromoindole (3.0 g, 8.51 mmol) was combined withPdCl₂(dppf) at −78° C. and stirred for 5 minutes before Ethylmagnesiumbromide (EtMgBr; 12.8 mL, 12.81 mmol) was added. The mixture was allowedto warm to room temperature. Toluene (15 mL) was added to the reactionmixture and heated at reflux for 1 hour. The reaction mixture wasallowed to cool to room temperature and was quenched with 2N H₃PO₄. Themixture was extracted with EtOAc and washed with brine, dried overMgSO₄, filtered and evaporated to give compound 9 as an oil (5%EtOAc/Hexanes) to give (2.3 g; 90% yield; +1=302.5).

Step 3-Preparation of 5-Ethyl-1H-indole 10

The Indole 9 (2.2 g, 7.29 mmol) was dissolved in THF (20 mL) and asolution of ammonium fluoride (NH₄F; 1.4 g, 37.8 mmol) in MeOH (20 mL)was added and stirred for 72 hours at room temperature. The solvent wasevaporated and the residue was dissolved in ethyl acetate. The organiclayer was washed with 2N H₃PO₄, dried over MgSO₄, filtered andevaporated to give compound 10 as an off white solid (1.06 g;M+1=146.2). U.S. Pat. No. Step 4-Preparation of(5-Ethyl-1H-indol-3-ylmethyl)-dimethyl-amine 11.

5-Ethylindole 10 (1.0 g, 6.89 mmol) was combined with isopropyl alcohol(200 mL), N,N-dimethylamine hydro chloride (718 mg, 6.95 mmol) andaqueous formaldehyde (37%, 589 mg, 6.95 mmol) and heated at reflux for 2hours. The reaction mixture was allowed to cool to room temperature, thesolvent was evaporated and the resulting residue was dissolved in EtOAcand washed with saturated NaHCO₃. The organic layer was dried overMgSO₄, filtered and evaporated to give compound II as a solid in (1.35 gfor a 97% yield; M+1=203.2)

Step 5-Preparation of 2-(5-Ethyl-1H-indol-3-ylmethyl)-malonic aciddiethyl ester 12

The 5-Ethylgramine (1.25 g, 6.18 mmol) was combined with diethylmalonate (2.85 mL, 18.54 mmol) and heated to 120° C. until a homogeneoussolution was formed. To this mixture was added sodium metal (100 mg,4.36 mmol) and the mixture was stirred at 120° C. for 24 hours. TLCindicated the completion of the reaction. The reaction was allowed tocool to room temperature and a solution of 5% HCl (aqueous) was slowlyadded to the mixture and the resulting product was extracted with EtOAc.The organic layer was washed with saturated sodium bicarbonate, driedover anhydrous magnesium sulafate, filtered and evaporated to givecompound 12 as a white solid (1.67 g; 85% yield; M+1=318.4). The productwas taken into the next step without purification.

Step 6-Preparation of 2-(5-Ethyl-1H-indol-3-ylmethyl)-malonic acid 13

The crude diethyl malonylindole 12 (1.67 g, 5.26 mmol) was dissolved inTHF (20 mL) and a solution of NaOH (1.0 g, 25.5 mmol) in H₂O (20 mL) wasadded. MeOH (5 mL) was also added to the reaction to make the solutionhomogeneous. The mixture was warmed to 50° C. and stirred overnight. Themixture was allowed to cool to room temperature, the organic layer wasevaporated and the residue was acidified with 2N H₃PO₄, and the productwas extracted with a mixture of 3:1/CHCl₃:MeOH. The organic layer waswashed with brine, dried over MgSO₄, filtered, and evaporated to givethe crude diacid as a white solid (1.25 g; M −1=260.2). The product wastaken into the next step without purification.

Step 7-Preparation of 3-(5-Ethyl-1H-indol-3-yl)-propionic acid 14

The crude malonic acid 13 (250 mg, 0.957 mmol) was placed in a roundbottom flask under vacuum and slowly heated to between 150 and 200° C.,as the evolution of CO₂ occurred. As the bubbling ended, the reactionwas heated for 2 more additional minutes, then allowed to cool to roomtemperature. The product was purified by flash chromatography threetimes using 0 to 10% MeOH in CHCl₃ to give compound 14 as a solid (120mg; 57.7% yield; M−1=216.3).

Step 8-Preparation of3-(1-Benzenesulfonyl-5-ethyl-1H-indol-3-yl)-propionic acid 6

The indole propionic acid 14 (100 mg, 0.46 mmol) was dissolved in THF(5.0 mL) and cooled to −78° C. To this solution was added n-butyllithium(n-BuLi; 0.4 mL, 1.0 mmol, 2.4 M in hexanes) dropwise and the mixturewas stirred at −78° C. for 1 hour. To this mixture was addedbenzenesulfonyl chloride (0.13 mL, 1 mmol) and the reaction was allowedto stir overnight and warm to room temperature. The mixture was pouredinto ice cold H₃PO₄ and extracted with EtOAc. The organic layer wasdried over MgSO₄, filtered and evaporated. The residue was purified byflash chromatography (5% MeOH/CHCl₃) to give compound 6 as a white solid(10 mg; M−1=356.4).

Example 5 Synthesis of Indazole-3-propionic acid 16

Indazole-3-propionic acid 16 was prepared from commercially availableindazole-3-carboxylic acid 17 in 5 steps as described in Scheme 9.

Step 1-Preparation of (1H-Indazo-3-yl)-methanole 18

To a cooled solution of indazole-3-carboxylic acid 17 (3.95 g, 24.4mmol) in tetrahydrofuran (THF, 300 ml) under nitrogen, lithium aluminumhydride (LAH; 1.9 g, 50.5 mmol) was added in one portion. The resultingalcohol 17 was isolated through quenching the reactive LAH with water,until no hydrogen evolution was observed and the solution was thenfiltered, washed with THF, and concentrated to give alcohol 18 as alight brown solid (2.63 g, 72%).

Step 2-Preparation of Indazole-3-carboxyaldehyde 19

Manganese (II) oxide (6.4 g, 73 mmol) was added to a solution of(1H-indazol-3-yl)-methanol 18 (1.08 g, 7.4 mmol) in a mixture of DCM (40ml) and THF (30 ml). The solution stirred for 16 hours at ambienttemperature and filtered through celite and concentrated under reducedpressure to yield a white solid (0.65 g, 61%).

Step 3-Preparation of 3-(Indazo-3-yl)-propenoic acid methyl ester 20

3-(Indazo-3-yl)-propenoic acid methyl ester 20 was prepared fromaldehyde 19, as described in Step 1, Example 3.

Step 4-Preparation of Indazole-3-propionic acid methyl ester 21

Indazole-3-propionic acid methyl ester was prepared from compound 20 asdescribed in Step 2, Example 3.

Step 5-Preparation of Indazole-3-propionic acid 16

Indazole-3-propionic acid was prepared through saponification ofcompound 21 as described in Step 4, Example 3 (M−1=197.1).

Example 6 Synthesis of5-isopropoxy-3-(1-Benzene-sulfonyl-indol-3-yl)-propionic acid 22

Propionic acid 22 was prepared from commercially available5-hydroxy-indole 23 in 5 steps as shown in Scheme 10.

Step 1-Synthesis of 5-Isopropoxy-indole 24

To a solution of 5-hydroxyindole 23 (2.0 g, 0.015 mol) in 20 ml ofacetonitrile, anhydrous potassium carbonate (4 grams, 0.028 mol) wasadded and stirred vigorously before isopropyl iodide (3 grams, 0.018mol) was added. The reaction was stirred for 2 days at room temperatureand the solid was washed with acetonitrile. The filtrate wasconcentrated and purified with flash-chromatography (80% n-hexane/20%ethyl acetate) to give the desired product 24 as a light-yellowish oil(1.72 g, 83%; M+1=176.1).

Step 2-Synthesis of 5-Isopropoxy gramine 25

The 5-Isopropoxy gramine 25 was prepared from 5-Isopropoxy-indole 24 asdescribed in Step 2, Example 4 (M+1=233.4).

Step 3-Synthesis of 2-(5-Isopropoxy-1H-Indol-3-ylmethyl)-malonic aciddiethyl ester 26

Compound 26 was prepared from 25 as described in Step 3, Example 4(M+1=348.5).

Step 4-Synthesis of 5-Isopropoxy-indole-3-propionic acid 27

5-Isopropoxy-indole-3-propionic acid 27 was prepared from compound 26through the same protocol as described in Step 4, Example 4 (M−1=246.2).

Step 5-Synthesis of5-isopropoxy-3-(1-Benzene-sulfonyl-indol-3-yl)-propionic acid 22

To a cooled (−78° C.) solution of propionic acid (27) (96.3 mg, 0.510mmol) in tetrahydrofuran (10 ml), n-butyl lithium (1.40 ml, 2.24 mol)was added next and stirred for 30 minutes at −78° C. Benzene sulfonylchloride (277 mg, 1.5 mmol) was added next, and the reaction was stirredfor 16-24 hours, allowing temperature to rise from −78° C. to ambientconditions. The reaction was then diluted with ethyl acetate, and 1M HClwas added to adjust the pH to 1-2. The layers were then separated, andthe organic layer was placed over magnesium sulfate and concentratedunder reduced pressure. The crude material was then purified by flashchromatography with silica, eluting with 5% methanol in dichloromethaneto yield the desire product (22) as a white solid. (M−1=386.4)

Example 7 Preparation of Indole-3-propionic acid 28

Indole-3-propionic acid 28 was prepared through the commerciallyavailable indole-3-carboxyaldehyde as described in Example 3. (M−1,188.2)

Example 8 Preparation of3-(1-Benzenesulfonyl-5-methoxy-1H-indol-3-yl)-propionic acid 29

The 3-(1-benzenesulfonyl-5-methoxy-1H-indol-3-yl)-propionic acid 29 wasprepared using the same protocol as in example 3, substituting4-methoxybenzene sulfonyl chloride with benzene sulfonyl chloride,(M−1=358.4)

Example 9 Synthesis of3-[5-Methoxy-1-(3-methoxy-benzyl)-1H-indol-3-yl]-propionic acid 30

3-[5-Methoxy-1-(3-methoxy-benzyl)-1H-indol-3-yl]-propionic acid 30 wasprepared using the same protocol as in example 3, substituting4-methoxybenzene sulfonyl chloride with 3-methoxybenzyl bromide,(M−1=336.4)

Example 10 Synthesis of3-[1-(3-Chloro-benzyl)-5-methoxy-1H-indol-3-yl]-propionic acid 31

3-[1-(3-Chloro-benzyl)-5-methoxy-1H-indol-3-yl]-propionic acid 31 wasprepared using the same protocol as in example 3, substituting4-methoxybenzene sulfonyl chloride with 3-chlorobenzyl bromide,(M−1=322.4).

Example 11 Synthesis of3-[1-(4-Fluoro-benzyl)-5-methoxy-1H-indol-3-yl]-propionic acid 32

3-[1-(4-Fluoro-benzyl)-5-methoxy-1H-indol-3-yl]-propionic acid 32 wasprepared using the same protocol as in example 3, substituting4-methoxybenzene sulfonyl chloride with 4-fluorobenzyl bromide,(M−1=326.6).

Example 12 Preparation of3-[1-(4-Chloro-benzyl)-5-methoxy-1H-indol-3-yl]-propionic acid 33

3-[1-(4-Chloro-benzyl)-5-methoxy-1H-indol-3-yl]-propionic acid 33 wasprepared using the same protocol as in example 3, substituting4-methoxybenzene sulfonyl chloride with 4-chlorobenzyl bromide.(M−1=342.8)

Example 13 Synthesis of3-[5-Methoxy-1-(2-methoxy-benzyl)-1H-indol-3-yl]-propionic acid 34

3-[5-Methoxy-1-(2-methoxy-benzyl)-1H-indol-3-yl]-propionic acid 34 wasprepared using the same protocol as example 3, substituting4-methoxybenzene sulfonyl chloride with 2-methoxybenzyl bromide.(M−1=338.4)

Example 14 Synthesis of3-[5-Methoxy-1-(2-trifluoromethoxy-benzyl)-1H-indol-3-yl]-propionic acid35

3-[5-Methoxy-1-(2-trifluoromethoxy-benzyl)-1H-indol-3-yl]-propionic acid35 was prepared using the same protocol as in example 3, substituting4-methoxybenzene sulfonyl chloride with 2-trifluoromethoxybenzylbromide, (M−1=392.3).

Example 15 Synthesis of3-[5-Methoxy-1-(3-trifluoromethoxy-benzyl)-1H-indol-3-yl]-propionic acid36

3-[5-Methoxy-1-(3-trifluoromethoxy-benzyl)-1H-indol-3-yl]-propionic acid36 was prepared using the same protocol as in example 3, substituting4-methoxybenzene sulfonyl chloride with 3-trifluoromethoxybenzylbromide, (M−1=392.4).

Example 16 Synthesis of3-(1-Ethylthiocarbamoyl-5-methoxy-1H-indol-3-yl)-propionic acid 37

3-(1-Ethylthiocarbamoyl-5-methoxy-1H-indol-3-yl)-propionic acid 37 wasprepared using the same protocol as in example 3, substituting4-methoxybenzene sulfonyl chloride with ethyl isothiocyanate,(M−1=305.4).

Example 17 Synthesis of3-[5-Methoxy-1-(toluene-4-sulfonyl)-1H-indol-3-yl]-propionic acid 38

3-[5-Methoxy-1-(toluene-4-sulfonyl)-1H-indol-3-yl]-propionic acid 38 wasprepared using the same protocol as in example 3, substituting4-methoxybenzene sulfonyl chloride with 4-tolyl sulfonyl chloride,(M−1=373.4).

Example 18 Synthesis of 3-(1-Benzenesulfonyl-1H-indazol-3-yl)-propionicacid 39

3-(1-Benzenesulfonyl-1H-indazol-3-yl)-propionic acid 39 was preparedthrough the same protocol as in Step 5, Example 6, (M−1=329.4).

Example 19 Synthesis of3-[1-(4-Isopropyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionicacid methyl ester 40

3-[1-(4-Isopropyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionicacid methyl ester 40 was prepared using the same protocol as in example3, substituting 4-methoxybenzenesulfonyl chloride with4-isopropylbenzenesulfonyl chloride, (M+1=416.6).

Example 20 Synthesis of3-[1-(4-Isopropyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionicacid 41

3-[1-(4-Isopropyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionicacid was prepared through the saponification protocol with3-[1-(4-Isopropyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionicacid methyl ester 41 as described in step 4 of example 3, (M−1=400.5).

Example 21 Synthesis of3-[1-(4-Butoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acidmethyl ester 42

3-[1-(4-Butoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acidmethyl ester 42 was prepared using the same protocol as example 3,substituting 4-methoxybenzenesulfonyl chloride with4-n-butoxybenznesulfonyl chloride (M+1=446.5)

Example 22 Synthesis of3-[1-(4-Butoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid43

3-[1-(4-Butoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acidwas prepared through the saponification protocol with-[1-(4-Butoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acidmethyl ester 42 as described in step 4 of example 3, (M−1=430.5).

Example 23 Synthesis of3-[5-Methoxy-1-(4-trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionicacid methyl ester 44

3-[5-Methoxy-1-(4-trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionicacid methyl ester was prepared using the same protocol as in example 3,substituting 4-methoxybenzenesulfonyl chloride with4-trifluoromethoxybenzene sulfonyl chloride, (M+1=457.4).

Example 24 Synthesis of3-[5-Methoxy-1-(4-trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionicacid 45

3-[5-Methoxy-1-(4-trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionicacid was prepared through the saponification protocol with3-[5-Methoxy-1-(4-trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionicacid methyl ester 45 as described in step 4 of example 3, (M−1=442.4).

Example 25 Synthesis of3-[5-Methoxy-1-(4-phenoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acidmethyl ester 46

3-[5-Methoxy-1-(4-phenoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acidmethyl ester 45 as prepared using the same protocol as example 3,substituting 4-methoxybenzenesulfonyl chloride with 4-phenoxybenzenesulfonyl chloride, (M+1=466.6).

Example 26 Synthesis of3-[5-Methoxy-1-(4-phenoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid47

3-[5-Methoxy-1-(4-phenoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acidwas prepared through the saponification protocol with3-[5-Methoxy-1-(4-phenoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acidmethyl ester 46 as described in step 4 of example 3, (M−1=450.5).

Example 27 Synthesis of3-[1-(4-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acidmethyl ester 48

3-[1-(4-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acidmethyl ester 48 was prepared using the same protocol as in example 3,substituting 4-methoxybenzene sulfonyl chloride with 4-chlorobenzenesulfonyl chloride (M+1=406.9).

Example 28 Synthesis of3-[1-(4-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid49

3-[1-(4-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid49 was prepared through the saponification protocol with3-[1-(4-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acidmethyl ester 48 as described in step 4 of example 3, (M−1=392.9).

Example 29 Synthesis of3-[1-(4-Cyano-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acidmethyl ester 50

3-[1-(4-Cyano-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acidmethyl ester 50 was prepared using the same protocol as example 3,substituting 4-methoxybenzene sulfonyl chloride with 4-cyanobenzenesulfonyl chloride. (M+1=399.4)

Example 30 Synthesis of3-[1-(4-Cyano-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid51

3-[1-(4-Cyano-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid51 was prepared through the saponification protocol with3-[1-(4-Cyano-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acidmethyl ester 50 as described in step 4 of example 3, (M−1=383.4).

Example 31 Synthesis of3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionicacid methyl ester 52

3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionicacid methyl ester 52 was prepared using the same protocol as in example3, substituting 4-methoxybenzene sulfonyl chloride with3,4-dichlorobenzene sulfonyl chloride, (M+1=443.3).

Example 32 Synthesis of3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionicacid 53

3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionicacid

53 was prepared through the saponification with3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionicacid methyl ester 52 as described in step 4 of example 3, (M−1=427.3).

Example 33 Synthesis of3-[5-Methoxy-1-(4-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]-propionicacid methyl ester 54

3-[5-Methoxy-1-(4-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]-propionicacid methyl ester 54 was prepared using the same protocol as in example3, substituting 4-methoxybenzenesulfonyl chloride withtrifluoromethylbenzene sulfonyl chloride, (M+1=442.4).

Example 34 Synthesis of3-[5-Methoxy-1-(4-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]-propionicacid 55

3-[5-Methoxy-1-(4-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]-propionicacid 55 was prepared through the saponification of3-[5-Methoxy-1-(4-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]-propionicacid methyl ester 54 as described in step 3 of example 3, (M+1=404.5).

Example 35 Synthesis of3-[1-(4-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acidmethyl ester 56

3-[1-(4-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acidmethyl ester 56 was prepared using the same protocol as example 3,substituting 4-methoxybenzene sulfonyl chloride with 4-fluorobenzenesulfonyl chloride, (M+1=392.4).

Example 36 Synthesis of3-[1-(4-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid57

3-[1-(4-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid57 was prepared through the saponification of the3-[1-(4-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acidmethyl ester 56 as described in step 4 of example 3, (M−1=376.4).

Example 37 Synthesis of3-[5-Methoxy-1-(3-phenoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acidmethyl ester 58

3-[5-Methoxy-1-(3-phenoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acidmethyl ester 58 was prepared using the same protocol as in example 3,substituting 4-methoxybenzenesulfonyl chloride with 3-phenoxybenzenesulfonyl chloride, (M+1=466.5).

Example 38 Synthesis of3-[5-Methoxy-1-(3-phenoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid59

3-[5-Methoxy-1-(3-phenoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid59 was prepared through the saponification of3-[5-Methoxy-1-(3-phenoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acidmethyl ester 58 as described in step 4 of example 3, (M−1=376.4).

Example 39 Synthesis of3-[1-(3-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acidmethyl ester 60

3-[1-(3-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acidmethyl ester 60 was prepared using the same protocol as in example 3,substituting 4-methoxybenzene sulfonyl chloride with 3-fluorobenzenesulfonyl chloride, (M+1=392.3).

Example 40 Synthesis of3-[1-(3-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid61

3-[1-(3-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid61 was prepared through saponification of3-[1-(3-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acidmethyl ester 60 as described in step 4 of example 3, (M−1=376.4).

Example 41 Synthesis of3-[5-Methoxy-1-(toluene-3-sulfonyl)-1H-indol-3-yl]-propionic acid methylester 62

3-[5-Methoxy-1-(toluene-3-sulfonyl)-1H-indol-3-yl]-propionic acid methylester was prepared using the same protocol as in example 3, substituting4-methoxybenzenesulfonyl chloride with 3-tolyl sulfonyl chloride,(M+1=388.5).

Example 42 Synthesis of3-[5-Methoxy-1-(toluene-3-sulfonyl)-1H-indol-3-yl]-propionic acid 63

3-[5-Methoxy-1-(toluene-3-sulfonyl)-1H-indol-3-yl]-propionic acid 63 wasprepared through the saponification of3-[5-Methoxy-1-(toluene-3-sulfonyl)-1H-indol-3-yl]-propionic acid methylester 62 as described in step 4 of example 3, (M−1=372.4).

Example 43 Synthesis of3-[1-(3-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acidmethyl ester 64

3-[1-(3-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acidmethyl ester 64 was prepared using the same protocol as in example 3,substituting 4-methoxybenzenesulfonyl chloride with 3-chlorobenzenesulfonyl chloride, (M+1=408.9).

Example 44 Synthesis of3-[1-(3-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid65

3-[1-(3-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid65 was prepared through the saponification of3-[1-(3-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acidmethyl ester 64 as described in step 4 of example 3, (M−1=392.7).

Example 45 Synthesis of3-[5-Methoxy-1-(3-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acidmethyl ester 66

3-[5-Methoxy-1-(3-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acidmethyl ester 66 was prepared using the same protocol as in example 3,substituting 4-methoxybenzenesulfonyl chloride with 3-methoxybenzenesulfonyl chloride, (M+1=404.5).

Example 46 Synthesis of3-[5-Methoxy-1-(3-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid67

3-[5-Methoxy-1-(3-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid67 was prepared through the saponification of3-[5-Methoxy-1-(3-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acidmethyl ester 66 as described in step 4 of example 3, (M−1=388.4).

Example 47 Synthesis of3-[5-Methoxy-1-(3-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]-propionicacid methyl ester 68

3-[5-Methoxy-1-(3-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]-propionicacid methyl ester 68 was prepared using the same protocol as in example3, substituting 4-methoxybenzene sulfonyl chloride with3-trifluoromethylbenzene sulfonyl chloride, (M+1=442.4).

Example 48 Synthesis of3-[5-Methoxy-1-(3-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]-propionicacid 69

3-[5-Methoxy-1-(3-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]-propionicacid 69 was prepared through the saponifcation of3-[5-Methoxy-1-(3-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]-propionicacid methyl ester 68 as described in step 4 of example 3, (M−1=426.4).

Example 49 Synthesis of 3-(1-Benzyl-5-methoxy-1H-indol-3-yl)-propionicacid methyl ester 70

3-(1-Benzyl-5-methoxy-1H-indol-3-yl)-propionic acid methyl ester 70 wasprepared using the same protocol as example 3, substituting4-methoxy-benzenesulfonyl chloride with benzyl bromide, (M+1=324.4).

Example 50 Synthesis of 3-(1-Benzyl-5-methoxy-1H-indol-3-yl)-propionicacid 71

3-(1-Benzyl-5-methoxy-1H-indol-3-yl)-propionic acid 71 was preparedthrough the saponification of3-(1-Benzyl-5-methoxy-1H-indol-3-yl)-propionic acid methyl ester 70 asdescribed in step 4 of example 3, (M+1=308.3).

Example 51 Synthesis of3-[5-Methoxy-1-(thiophene-2-sulfonyl)-1H-indol-3-yl]-propionic acidmethyl ester 72

3-[5-Methoxy-1-(thiophene-2-sulfonyl)-1H-indol-3-yl]-propionic acidmethyl ester 72 was prepared using the same protocol as example 3,substituting 4-methoxybenzene sulfonyl chloride with 2-thiopene sulfonylchloride, (M+1=380.5). Example 52 Synthesis of3-[5-Methoxy-1-(thiophene-2-sulfonyl)-1H-indol-3-yl]-propionic acid 73

3-[5-Methoxy-1-(thiophene-2-sulfonyl)-1H-indol-3-yl]-propionic acid wasprepared through the saponification of3-[5-Methoxy-1-(thiophene-2-sulfonyl)-1H-indol-3-yl]-propionic acidmethyl ester as described in step 4 of example 3, (M−1=364.4).

Example 53 Synthesis of3-(5-Methoxy-1-phenylthiocarbamoyl-1H-indol-3-yl)-propionic acid methylester 74

3-(5-Methoxy-1-phenylthiocarbamoyl-1H-indol-3-yl)-propionic acid methylester 74 was prepared using the same protocol as example 3, substituting4-methoxybenzene sulfonyl chloride with phenyl isothiocyanate,(M+1=369.5).

Example 54 Synthesis of3-(5-Methoxy-1-phenylthiocarbamoyl-1H-indol-3-yl)-propionic acid 75

3-(5-Methoxy-1-phenylthiocarbamoyl-1H-indol-3-yl)-propionic acid 75 wasprepared through the saponification of3-(5-Methoxy-1-phenylthiocarbamoyl-1H-indol-3-yl)-propionic acid methylester 74 as described in step 4 of example 3, (M−1=353.4).

Example 55 Synthesis of3-[1-(4-Butyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acidmethyl ester 76

3-[1-(4-Butyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acidmethyl ester 76 was prepared using the same protocol as example 3,substituting 4-methoxybenzene sulfonyl chloride with 4-n-butylbenzenesulfonyl chloride, (M+1=430.2).

Example 56 Synthesis of3-[1-(4-Butyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid77

3-[1-(4-Butyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid77 was prepared through the saponification of3-[1-(4-Butyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acidmethyl ester 76 as described in step 4 of example 3, (M−1=414.1).

Example 57 Synthesis of3-[5-Methoxy-1-(3-trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionicacid methyl ester 78

3-[5-Methoxy-1-(3-trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionicacid methyl ester 78 was prepared using the same protocol as example 3,substituting 4-methoxybenzene sulfonyl chloride with 3-trifluorobenzenesulfonyl chloride (M+1=458.1).

Example 58 Synthesis of3-[5-Methoxy-1-(3-trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionicacid 79

3-[5-Methoxy-1-(3-trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionicacid 79 was prepared through the saponification of3-[5-Methoxy-1-(3-trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionicacid methyl ester 4 as described in step 4 of example 3, (M−1=442.0).

Example 59 Synthesis of 3-(1-Benzoyl-5-methoxy-1H-indol-3-yl)-propionicacid methyl ester 80

3-(1-Benzoyl-5-methoxy-1H-indol-3-yl)-propionic acid methyl ester 80 wasprepared using the same protocol as example 3, substituting4-methoxybenzene sulfonyl chloride with benzoyl chloride, (M+1=338.1).

Example 60 Synthesis of 3-(1-Benzoyl-5-methoxy-1H-indol-3-yl)-propionicacid 81

3-(1-Benzoyl-5-methoxy-1H-indol-3-yl)-propionic acid 81 was preparedthrough the saponification of3-(1-Benzoyl-5-methoxy-1H-indol-3-yl)-propionic acid methyl ester

80 as described in step 4 of example 3, (M−1=322.1).

Example 61 Synthesis of3-(1-Benzenesulfonyl-5-ethoxy-1H-indol-3-yl)-propionic acid 82

3-(1-Benzenesulfonyl-5-ethoxy-1H-indol-3-yl)-propionic acid 83 wasprepared using the same protocol as example 6, substituting 2-propyliodide with ethyl iodide, (M−1=372.4).

Example 62 Synthesis of3-[1-(4-Isopropoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionicacid 83

3-[1-(4-Isopropoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionicacid 83 was prepared using the same protocol as example 3, substituting4-methoxybenzene sulfonyl chloride with 4-isopropoxybenzene sulfonylchloride, (M−1=416.5).

Example 63 Synthesis of3-(5-Methoxy-1-phenylcarbamoyl-1H-indol-3-yl)-propionic acid methylester 84

3-(5-Methoxy-1-phenylcarbamoyl-1H-indol-3-yl)-propionic acid methylester 84 was prepared using the same protocol as example 3, substituting4-methoxybenzene sulfonyl chloride with phenyl isocyanate, (M+1=353.4).

Example 64 Synthesis of3-(5-Methoxy-1-phenylcarbamoyl-1H-indol-3-yl)-propionic acid 85

3-(5-Methoxy-1-phenylcarbamoyl-1H-indol-3-yl)-propionic acid 85 wasprepared through the saponifcation of3-(5-Methoxy-1-phenylcarbamoyl-1H-indol-3-yl)-propionic acid methylester 84 as described in step 4 of example 3, (M−1=337.4).

Example 65 Synthesis of3-[1-(4-Ethyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid86

3-[1-(4-Ethyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid86 was prepared using the same protocol as example 3, substituting4-methoxybenzene sulfonyl chloride with 4-ethylbenzene sulfonylchloride, (M−1=386.4).

Example 66 Synthesis of 3-(5-bromo-1H-indol-3-yl)-propionic acid 87

3-(5-bromo-1H-indol-3-yl)-propionic acid 87 was prepared fromcommercially available 5-Bromoindole using the same protocol as inexample 6 to give a beige solid, (M−1=268.0).

Example 67 Synthesis of 3-(5-Bromo-1H-indol-3-yl)-propionic acid methylester 88

The 5-bromoindole-3-propionic acid 87 (4.0 g, 14.91 mmol) was dissolvedin methanol (MeOH, 100 mL) and Trimethylsilyl chloride (TMSCl, 33.0 mL,32.8 mmol, 1.0 M in CH₂Cl₂) was added dropwise The mixture was stirredfor 24 hours, followed by refluxing for 1 hour. The reaction was allowedto cool to room temperature and the solvent was evaporated to ester as awhite solid, (M+1=284).

Example 68 Synthesis of3-(1-Benzenesulfonyl-5-bromo-1H-indol-3-yl)-propionic acid methyl ester89

3-(1-Benzenesulfonyl-5-bromo-1H-indol-3-yl)-propionic acid methyl ester89 prepared as described in step 3 of example 3 by substituting4-methoxy-benzenesulfonyl chloride with benzenesulfonyl chloride,(M+1=424).

Example 69 Synthesis of3-(1-Benzenesulfonyl-5-bromo-1H-indol-3-yl)-propionic acid methyl ester90

3-(1-Benzenesulfonyl-5-bromo-1H-indol-3-yl)-propionic acid 90 wasprepared through the saponifcation methyl ester 89 using the procedureas described in step 4 of example 3, (M−1=406.0).

Example 70 Synthesis of3-(Benzenesulfonyl-5-thiophen-3-yl-1H-indol-3-yl)-propionic acid methylester 91

3-(1-Benzenesulfonyl-5-bromo-1H-indol-3-yl)-propionic acid methyl ester89 (200 mg, 0.474 mmol) was combined with 3-thienyl boronic acid (67.0mg, 0.52 mmol), triphenylphosphine (9.0 mg, 0.03 mmol), Pd(OAc)₂ (4.0mg, 0.015 mmol), K₂CO₃ (90 mg, 0.65 mmol), 1,2-Dimethoxyethane (DME, 4.0mL) and H₂O (0.4 mL) and was heated at 90° C. for 48 hours. The reactionwas allowed to cool to room temperature and the solvent was evaporated.The resulting residue was dissolved in EtOAc and washed with brine. Theorganic layer was dried over MgSO₄, filtered, and evaporated. Theresidue was purified with flash silica gel chromatography (20%EtOAc/Hexanes) to obtain the ester 91 as a white solid, (110 mg,M+1=426.1).

Example 71 Synthesis of3-(Benzenesulfonyl-5-thiophen-3-yl-1H-indol-3-yl)-propionic acid 92

3-(Benzenesulfonul-5-thiophen-3-yl-1H-indol-3-yl)-propionic acid 92 wasprepared through the saponifcation of methyl ester 91 as described instep 4 of example 3, (M−1=410.1).

Example 72 Synthesis of 3-(1-Benzenesulfonyl-5-pheyl-1H-indol-3-yl)propionic acid methyl ester 93

The ester 93 was prepared from the methyl ester 89 by following theprocedure as described in example 70 by substituting 3-Thienyl boronicacid with Phenyl boronic acid, (M+1=420).

Example 73 Synthesis of 3-(1-Benzenesulfonyl-5-pheyl-1H-indol-3-yl)propionic acid 94

3-(1-Benzenesulfonyl-5-pheyl-1H-indol-3-yl) propionic acid 94 wasprepared through the saponifcation of methyl ester 94 as described instep 4 of example 3, (M−1=404.5).

Example 74 Preparation of 3-(1H-Pyrrolo[2,3-b]pyridine-3-yl)-propionicacid 95

3-(1H-Pyrrolo[2,3-b]pyridine-3-yl)-propionic acid 95 was prepared fromcommercially available 7-azaindole by the same protocol described insteps 4-6 of example 4, (M−1=189.2).

Example 75 Synthesis of 3-(5-Methoxy-1H-Indol-3-yl)-propionic acid 96

3-(5-Methoxy-1H-Indol-3-yl)-propionic acid 96 was prepared fromsaponification of 3-(5-methoxy-1H-indol-3-yl)-propionic acid methylester 4 as described in step 4 of Example 3. (M−1=218.2)

Example 76 Synthesis of 3-(1-Benzenesulfonyl-1H-indol-3-yl)-propionicacid 97

3-(1-Benzenesulfonyl-1H-indol-3-yl)-propionic acid 97 was prepared fromindole-3-propionic acid 28 using the protocol as described in step 8,Example 4. (M−1=329.4)

Example 77 Synthesis of3-(1-Benzenesulfonyl-5-methoxy-1H-indol-3-yl)-propionic acid methylester 98

3-(1-Benzenesulfonyl-5-methoxy-1H-indol-3-yl)-propionic acid methylester 98 was prepared using the same protocol as example 3, substituting4-methoxybenzene sulfonyl chloride with benzene sulfonyl chloride.(M+1=374.4)

Example 78 Synthesis of3-[5-Methoxy-1-(thiophene-3-sulfonyl)-1H-indol-3-yl]-propionic acid 99

3-[5-Methoxy-1-(thiophene-3-sulfonyl)-1H-indol-3-yl]-propionic acid 99was prepared from 3-(5-methoxy-1H-indol-3-yl)-propionic acid 96 and3-thienyl-sulfonyl chloride using the same protocol as described in step8, Example 4. (M−1, 364.4)

Example 79 Synthesis of(1-Benzenesulfonyl-5-methoxy-1H-indol-3-yl)-acetic acid 100

(1-Benzenesulfonyl-5-methoxy-1H-indol-3-yl)-acetic acid 100 was preparedfrom commercially available (5-methoxy-1H-indol-3-yl)-acetic acid andbenzene sulfonyl chloride using the protocol as described in step 8,example 4. (M−1=344.4)

Step 1-Preparation of Compound of Formula XVIII

Compound XVIII can be prepared through coupling of compound III withbenzene sulfonyl chloride in a bi-phasic solvent condition e.g. tolueneand water, in presence of a base, e.g. an aqueous potassium hydroxidesolution with a phase transfer catalyst, e.g. tetrabutylammoniumhydrogen sulfate, similar to conditions as described Cribble et al, inJ. Org. Chem., 2002, 63, pg 1001-1003.

Step 2-Preparation of Compound XIX

Compound XIX was prepared through conventionally Knoevenagel reactionreacting compound XVIII with malonic acid piperidine in pyridine at 80°C. for 3-4 hours, as described in Vangvera et al in J. Med. Chem., 1998,41, pg 4995-5001.

Step 3-Preparation of Compound Ib

Compound Ia was prepared from compound XIX through reduction viacatalytic hydrogenation (typically with 10% palladium on activatedcarbon in an inert solvent (see preparation of intermediate II, videsupra).

Example 80 Alternate synthesis of3-[5-methoxy-1-(4-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid1

Step 1: Preparation of 1-(4-Methoxybenzenesulfonyl)-5-methoxy-1H-indole-3-carboxyaldehyde)(117)

To a dry round bottom flask, 5-methoxy indole-3-aldehyde 2 (1.0 g, 5.7mmol) was dissolved with toluene (4 mL). Tetrabutylammonium iodide (10mg) and 50% KOH solution (2 mL) were added next. After about 5 minutesof stirring, 4-methoxybenzene sulfonyl chloride (1.7 grams, 8.2 mmol)was added. Within 2-3 hours, solid began to precipitate out of thesolution. This reaction was allowed to stir at ambient temperature for 2hours, after which water (50 mL) and ethyl acetate (150 ml) was added tothe reaction. The layers were separated; the organic layer was washedwith saturated bicarbonate (3×75 mL) and water (4×75 mL) to ensureremoval of the hydroxide and sulfonate salt, and washed with brine (1×75ml) and dried over anhydrous sodium sulfate. Evaporation under reducedpressure afforded 117 as a light brown solid. (1.86 g, 94%) ¹H NMR(CDCl₃) δ 10.0 (s, 1H), 8.20 (s, 1H), 7.92 (d, J=9.2 Hz, 2H), 7.85 (d,J=8.8, 1H), 7.74 (d, J=2.4, 1H), 7.04 (dd, J=2.8 Hz, 9.2 Hz, 1H), 6.97(d, J=9.2 Hz, 2H), 3.85 (s, 3H).

Step 2: Preparation of 3-[1-(4-Methoxybenzenesulfonyl)-5-methoxy-1H-indol-3-yl]-acrylic acid (118)

To a solution of 1-(4-Methoxybenzenesulfonyl)-5-methoxy-1H-indole-3-carbaldehyde 5 (0.51 g, 1.5 mmol)dissolved in pyridine (10 mL), malonic acid (0.53 g, 5.1 mmol) andpiperidine, (1 mL) were combined in a reaction vessel. The yellowsolution was heated for 3 hours at 80° C. The reaction was allowed tocool to ambient temperature and diluted with 150 mL of ethyl acetate.The organic layer was washed with 1N HCl (6×50 mL) and saturated sodiumchloride solution (1×50 mL). After drying over sodium sulfate, theorganic layer was filtered through a pad of sodium sulfate andevaporated under reduced pressure to yield product 118 as an off-whitesolid. (0.521 g, 90%) ¹HNMR (CDCl₃) δ 7.86 (m, 5H), 7.2 (d, J=2.4 Hz,1H), 7.0 (dd, J=2.8 Hz, 9.2 Hz, 1H), 6.91 (d, J=8.8 Hz, 2H), 6.46 (d,J=16, 1H), 3.87 (s, 3H, CH₃) (M−1=386.2).

Step 3: Preparation of 3-[1-(4-Methoxybenzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid (1)

To a solution of 3-[1-(4-Methoxybenzenesulfonyl)-5-methoxy-1H-indol-3-yl]-acrylic acid 118 (1.0 g, 2.6mmol) dissolved in THF (14 mL), Pd/C (67 mg) was added in one portion.The solution was attached to the Parr hydrogenator. The reaction wasallowed to proceed overnight at 20-22 psi. The solution was filteredover celite, and the palladium-celite pad was washed with ethyl acetate(40 mL), and methanol (20 mL). The combined washes/solution wasevaporated under reduced pressure to afford straw colored oil thatsolidified after cooling under high vacuum. The crude was trituratedwith diethyl ether to leave behind off white solid as product 1. (0.620g, 62%) ¹H NMR (DMSO) δ 7.86 (d, J=9.2 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H),6.92 (dd, J=2.4 Hz, 9.2 Hz, 1H), 6.88 (s, 1H), 6.83 (d, J=9.2 Hz, 2H),3.76 (s, 3H), 2.96 (t, J=7.6 Hz, 14.8 Hz, 2H), 2.74 (t, J=7.6 Hz, 14.8Hz, 2H) (M−1=388.6).

Example 81 Synthesis of3-[5-Methoxy-1-(4-methoxy-benzenesulfonyl)-1H-indol-3-yl]-2,2-dimethyl-propionicacid 119

Step 1-Synthesis of 5-methoxy-1H-indol-3yl-methanol 141

To a solution of sodium borohydride (2 grams, 0.05 mol) in methanol (15ml), a solution of 5-methoxy-1H-indol-3-carboxaldehyde 2 (1 gram, 0.006mol) dissolved in THF (20 ml) and methanol (15 ml) were combined andstirred at ambient temperature for 16 hours. The reaction was dilutedwith water and potassium carbonate (to saturation) and stirred to quenchunreacted sodium borohydride. Diethyl ether was used to extract theproduct from the quenched solution. Following layers separation, theaqueous layer was further extracted (2×) with diethyl ether. Thecombined organic pats were dried over sodium sulfate and evaporated todryness to yield a light colored solid 141 (736 mg, 70%).

Step 2-Preparation of 3-(5-Methoxy-1H-indol-3-yl)-propionic acid methylester 142

To a solution of 5-methoxy-1H-indol-3-yl-methanol 141 (115 mg, 0.643mmol) dissolved in dichloromethane (3 ml),(1-methoxy-2-methyl-propenyloxy)-trimethylsilane (200 mg, 1 mmol) andmagnesium perchlorate (164 mg, 0.74 mmol) were added. The reaction wasallowed to stir at ambient temperature for 3-4 hours after which themixture was diluted with water (50 ml) and dichloromethane (DCM, 100mL). The organic layer was separated and washed with water (50 mL; 3×).The organic layer was washed once with brine, dried over anhydroussodium sulfate, and evaporated under reduced pressure to give an oil andpurified with flash chromatography (silica with 80% hexane, 20% ethylacetate to afford 142 as a light colored oil (150 mg; 88% yield;M+1=262.3).

Step 3-Preparation of3-[5-Methoxy-1-(4-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acidmethyl ester 120

To a cooled solution (0° C.) of indole-3-propionic acid methyl ester 142(0.110 g, 0.42 mmol) in DMF (3 mL) was added sodium hydride (60%; 0.030g; 0.75 mmol) was added in one portion and stirred for 30 min followedby the addition of 4-methoxybenzenesulfonyl chloride (0.200 g; 1.0mmol). The reaction was allowed to warm up to room temperature andstirred for 16 h, subjected to aqueous work up, and product wasextracted with ethyl acetate. The ethyl acetate layer was washed withbrine, dried over anhydrous sodium sulfate, evaporated under reducedpressure, and purified by flash-chromatography (silica gel; 85%n-hexane-15% ethyl acetate) to afford the methyl ester 120 as an oil(M+1=432.4). The methyl ester 120 was then taken on toward generation ofthe product.

Step 4-Preparation of3-[5-Methoxy-1-(4-methoxy-benzenesulfonyl)-1H-indol-3-yl]-2,2-dimethyl-propionicacid 119

To a solution of the methyl ester 120 in tetrahydrofuran (6 mL) wasadded an aqueous solution of potassium hydroxide (2 mL of 1M) andstirred at room temperature for 5 h. The acid 119 was isolated byneutralizing the reaction mixture by aqueous hydrochloric acid,extracting the product with ethyl acetate, drying over anhydrousmagnesium sulfate, evaporating under reduced pressure, and purifyingusing flash chromatography with 5% methanol in dichloromethane to afforda white solid (80 mg, 46% overall, M−1=416.5).

Example 82 Synthesis of3-[1-(3,4-Dimethoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionicacid 101

3-[1-(3,4-dimethoxybenzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionicacid 101 was prepared using the same protocol as in example 3,substituting 4-methoxybenzene sulfonyl chloride with3,4-dimethoxybenzenesulfonyl chloride, (M−1=418.5).

Example 83 Synthesis of3-[1-(3,4-Difluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionicacid 102

3-[1-(3,4-difluorobenzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionicacid 102 was prepared using the same protocol as in example 3,substituting 4-methoxybenzene sulfonyl chloride with3,4-difluorobenzenesulfonyl chloride, (M−1=395.3).

Example 84 Synthesis of3-[1-(3-chloro-4-methyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionicacid 103

3-[1-(3-chloro-4-methyl)-5-methoxy-1H-indol-3-yl]-propionic acid 103 wasprepared using the same protocol as in example 3, substituting4-methoxybenzene sulfonyl chloride with 3-chloro-4-methylbenzenesulfonylchloride, (M−1=406.8).

Example 85 3-[1-(benzenesulfonyl)-5-fluoro-1H-indol-3-yl]-propionic acid104

3-[1-(benzenesulfonyl)-5-fluoro-1H-indol-3-yl]-propionic acid 104 wasprepared using the same protocol as in example 3, substituting4-methoxybenzene sulfonyl chloride with benzenesulfonyl chloride,(M−1=346.5).

Example 86 Synthesis of3-[1-(benzenesulfonyl)-5-methyl-1H-indol-3-yl]-propionic acid 105

3-[1-(benzenesulfonyl)-5-methyl-1H-indol-3-yl]-propionic acid 105 wasprepared using the same protocol as in example 3, substituting4-methoxybenzene sulfonyl chloride with benzenesulfonyl chloride,(M−1=342.2).

Example 87 Synthesis of3-[1-(benzenesulfonyl)-5-chloro-1H-indol-3-yl]-propionic acid 106

3-[1-(benzenesulfonyl)-5-chloro-1H-indol-3-yl]-propionic acid 106 wasprepared using the same protocol as in example 3, substituting4-methoxybenzene sulfonyl chloride with benzenesulfonyl chloride,(M−1=362.7).

Example 88 Synthesis of3-[1-(3-fluoro-4-methyl-benzenesulfonyl)-5-chloro-1H-indol-3-yl]-propionicacid 107

3-[1-(3-fluoro-4-methyl-benzenesulfonyl)-5-chloro-1H-indol-3-yl]-propionicacid 107 was prepared using the same protocol as in example 3,substituting 4-methoxybenzene sulfonyl chloride with3-fluoro-4-methyl-benzenesulfonyl chloride, (M−1=390.3).

Example 89 Synthesis of3-[1-(2,3-Dihydro-benzofuran-5-sulfonyl)-5-methoxy-1H-indol-3-yl]-propionicacid 108

3-[1-(2,3-Dihydro-benzofuran-5-sulfonyl)-5-methoxy-1H-indol-3-yl]-propionicacid 108 was prepared using the same protocol as in example 3,substituting 4-methoxybenzene sulfonyl chloride with2,3-Dihydro-benzofuran-5-sulfonyl chloride, (M−1=400.2).

Example 90 Synthesis of3-[1-(4-ethyl-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid109

3-[1-(4-ethyl-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid109 was prepared using the same protocol as in example 3, substituting4-methoxybenzene sulfonyl chloride with 4-ethyl-benzenesulfonylchloride, (M−1=400.5).

Example 91 Synthesis of3-[1-(4-methoxy-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid110

3-[1-(4-methoxy-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid110 was prepared using the same protocol as in example 3, (M−1=402.6).

Example 92 Synthesis of3-[1-(3-trifluoromethoxy-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionicacid 111

3-[1-(3-trifluoromethoxy-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionicacid 111 was prepared using the same protocol as in example 3,substituting 4-methoxybenzene sulfonyl chloride with3-trifluoromethoxy-benzenesulfonyl chloride, (M−1=456.3).

Example 93 Synthesis of3-[1-(4-butyl-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid112

3-[1-(4-butyl-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid112 was prepared using the same protocol as in example 3, substituting4-methoxybenzene sulfonyl chloride 4-butyl-benzenesulfonyl chloride,(M−1=428.4).

Example 94 Synthesis of3-[1-(4-butoxy-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid113

3-[1-(4-butoxy-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid113 was prepared using the same protocol as in example 3, substituting4-methoxybenzene sulfonyl chloride 4-butoxy-benzenesulfonyl chloride,(M−1=444.5).

Example 95 Synthesis of3-[1-(3,4-dichloro-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionicacid 114

3-[1-(3,4-dichloro-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionicacid 114 was prepared using the same protocol as in example 3,substituting 4-methoxybenzene sulfonyl chloride3,4-dichloro-benzenesulfonyl chloride, (M−1=441.2).

Example 96 Synthesis of3-[1-(3-methoxy-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid115

3-[1-(3-methoxy-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid115 was prepared using the same protocol as in example 3, substituting4-methoxybenzene sulfonyl chloride 3-methoxy-benzenesulfonyl chloride,(M−1=402.5).

Example 97 Synthesis of3-[1-(4-phenoxy-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid116

3-[1-(4-phenoxy-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid116 was prepared using the same protocol as in example 3, substituting4-methoxybenzene sulfonyl chloride 4-phenoxy-benzenesulfonyl chloride,(M−1=464.3).

Example 98 Synthesis of3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-2,2-dimethyl-propionicacid methyl ester 122

3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-2,2-dimethyl-propionicacid methyl ester 122 was prepared using the same protocol as example 3,step 3, substituting 4-methoxy-benzenesulfonyl chloride with3,4-dichloro-benzenesulfonyl chloride (M+1=457.2).

Example 99 Synthesis of3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-2,2-dimethyl-propionicacid 121

3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-2,2-dimethyl-propionicacid methyl ester 121 was prepared from the corresponding methyl ester122, using the same protocol as example 3, step 4, (M+1=469.2).

Example 100 Synthesis of(E)-3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-acrylicacid 123

(E)-3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-acrylicacid 123 was prepared using the same protocol as in Scheme 12,substituting 4-methoxybenzene sulfonyl chloride3,4-dichlorobenzenesulfonyl chloride in step-1, (M−1=425.2).

Example 101 Synthesis of(E)-3-[1-(4-butyl-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-acrylic acid124

(E)-3-[1-(4-butyl-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-acrylic acid124 was prepared using the same protocol as in Scheme 12, substituting4-methoxybenzene sulfonyl chloride 4-butylbenzenesulfonyl chloride instep-1, (M−1=426.4).

Example 102 Synthesis of(E)-3-[1-(4-butoxy-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-acrylic acid125

(E)-3-[1-(4-butoxy-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-acrylic acid125 was prepared using the same protocol as in Scheme 12, substituting4-methoxybenzene sulfonyl chloride 4-butoxybenzenesulfonyl chloride instep-1, (M−1=442.4).

Example 103 Synthesis of3-[1-(3-Chloro-4-methoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionicacid 126

3-[1-(3-Chloro-4-methoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionicacid 126 was prepared using the same protocol as in Scheme 12,substituting 4-methoxybenzene sulfonyl chloride3-chloro-4-methoxy-benzenesulfonyl chloride in step-1, (M−1=423.0).3-Chloro-4-methoxy-benzenesulfonyl chloride was in turn prepared byreacting 2-chloroanisole with chlorosulfonic acid (neat at 0° C., 4 h)following the literature procedure (Cremlyn, R. J. W.; Hornby, R.; J.Chem. Soc. C; 1969; 1341-1345)

Example 104 Synthesis of Synthesis of3-[1-(4-Methoxy-benzenesulfonyl)-7-methyl-1H-indol-3-yl]-propionic acid127

Compound 127 is synthesized from commercially available7-methyl-lindole-3-carboxaldehyde following synthetic steps shown inScheme 12.

Example 105 Synthesis of3-[1-(4-Methoxy-benzenesulfonyl)-6-methyl-1H-indol-3-yl]-propionic acid128

Compound 128 is synthesized from commercially available6-methyl-indole-3-carboxaldehyde following synthetic steps shown inScheme 12.

Example 106 Synthesis of3-[1-(4-Methoxy-benzenesulfonyl)-6-fluoro-1H-indol-3-yl]-propionic acid129

Compound 129 is synthesized from commercially available6-fluoro-indole-3-carboxaldehyde following synthetic steps shown inScheme 12.

Example 107 Synthesis of3-[1-(4-Methoxy-benzenesulfonyl)-7-fluoro-1H-indol-3-yl]-propionic acid130

Compound 130 is synthesized from commercially available7-fluoro-indole-3-carboxaldehyde following synthetic steps shown inScheme 12.

Example 108 Synthesis of3-[1-(4-Methoxy-benzenesulfonyl)-4-chloro-7-fluoro-1H-indol-3-yl]-propionicacid 131

Compound 131 is synthesized from commercially available4-chloro-7-fluoro-indole-3-carboxaldehyde following synthetic stepsshown in Scheme 12.

Example 109 Synthesis of3-[1-(4-Methoxy-benzenesulfonyl)-6-methoxy-1H-indol-3-yl]-propionic acid132

Compound 132 is synthesized from 6-methoxy-indole-3-carboxaldehyde,which in turn is synthesized from commercially available6-methoxy-indole using Vilsmeier-Haack reaction (Advanced organicchemistry, Jerry March, 2^(nd) Ed. P715), following synthetic stepsshown in Scheme 12.

Example 110 Synthesis of3-[1-(4-Methoxy-benzenesulfonyl)-5,6-dimethoxy-1H-indol-3-yl]-propionicacid 133

Compound 133 is synthesized from 5,6-dimethoxy-indole-3-carboxaldehyde,which in turn is synthesized from commercially available5,6-dimethoxy-indole using Vilsmeier-Haack reaction (Advanced organicchemistry, Jerry March, 2^(nd) Ed. P715), following synthetic stepsshown in Scheme 12.

Example 111 Synthesis of3-[1-(4-Methoxy-benzenesulfonyl)-6-bromo-1H-indol-3-yl]-propionic acid134

Compound 134 is synthesized from commercially available6-bromo-indole-3-carboxaldehyde following synthetic steps shown inScheme 12.

Example 112 Synthesis of3-[1-(4-Methoxy-benzenesulfonyl)-5-methoxy-1H-indazol-3-yl]-propionicacid 135

Compound 135 is synthesized from commercially available5-methoxy-indazole-3-carboxylic acid following synthetic steps shown inScheme 9.

Example 113 Synthesis of3-[1-(4-Methoxy-benzenesulfonyl)-6-methoxy-1H-indazol-3-yl]-propionicacid 136

Compound 136 is synthesized from commercially available6-methoxy-indazole-3-carboxylic acid following synthetic steps shown inScheme 9.

Example 114 Synthesis of3-[1-(4-Methoxy-benzenesulfonyl)-5-methoxy-1H-7aza-indazol-3-yl]-propionicacid 137

Compound 137 is synthesized from aldehyde 138, prepared fromcommercially available 7-azainbdole as shown in Scheme 14, followingsynthetic steps shown in Scheme 12.

Compound 139, 5-bromo-7-azaindole, was prepared from commerciallyavailable 7-azaindole by following the procedure published by Mazeas,Daniel; Guillaumet, Gerald; Marie-Claude Viaud, Heterocycles, 1999, v50(2), 1065-1080. Compound 140 is prepared by heating the bromide 139 withsodium methoxide in dimethyl formamide in presence of cuprous bromide asdescribed by Mazeas, Daniel; Guillaumet, Gerald; Marie-Claude Viaud,Heterocycles, 1999, v50 (2), 1065-1080, from which the aldehyde 138 isprepared by Vilsmeier-Haack reaction.

Example 115 Synthesis of Analogs of Compound 1

Analogs of compound I can be synthesized, e.g., by using thecommercially available compounds shown in Table 3 as described inExample 3 or Example 109.

Synthesis of Carboxylic Acid Bioisosteres

The carboxylic acid functional group of the propionic acid moiety atposition 3 can advantageously be replaced with any of a number ofcarboxylic acid bioisosteres in compounds of Formula I. For example, thefollowing moieties can be used, which are shown with respect to FormulaI-1, but which can also be incorporated in other bicyclic rings systemswithin Formula I.

Thiazolidione (TZD) and Related Analogs:

Step 1

Compound XX can be prepared through a Knoevenagel coupling ofthiazolidione or related compounds in presence of an inert solvent, e.g.ethanol, with catalytic amount of piperidine with starting compound III.(L. Sun. et al, J. Med. Chem., 1999, 42, 5120-30.)

Step 2

Compound XXI can be prepared from compound XX through a reductionprocess using palladium on activated carbon, or a metal reductionreaction (e.g. magnesium). (B. C. Cantello, J. Med. Chem., 1994, 37,3977-85.)

Hydroxamic Acid:

Compound XXII can be prepared through either amide bond formationreaction with Ia or Ib or nucleophilic displacement of the ester II orIXa with n-hydroxyamine. (Hurd et al, J. Am. Chem. Soc., 1954, 76, 2791and Dinh, T. Q., Tet. Lett. 1996, 37, 1161-4).

Tetrazole:

Tetrazole isostere of the carboxylic acid can be prepared through 3steps from the corresponding acetic or propanoic acid (depending onlinker size).

Step 1

The conversion of the carboxylic acid moiety to the corresponding amideXXIII with compound Ia or Ib can be done with ammonia (gas) with ethylpolyphosphate in an inert solvent such as chloroform (Imamoto, T. et al,Synthesis, 1983, 142-3).

Step 2

The propionamide XXIII can be converted to the nitrile XXIV by treatingthe amide with methyl magnesium iodide (Wilson et al, J. Chem. Soc.,1923, 123, 2615) or with formic acid in acetonitrile (Heck, M.-P., J.Org. Chem., 1996, 61, 6486-7).

Step 3

The preparation of the tetrazole isostere involves coupling of the2-cyano-alkyl group with sodium azide in a cyclization reaction togenerate the desired compound XXV. (Juby et al, J. Med. Chem., 1969, 12,396-401).

Iso-Oxazoles:

Method 1:

The hydroxyiso-oxazole compound XXVIII can be derived in 5 steps. Usingstarting material indole-3-acetic acid XXVI, compound XXVII can beprepared through reactions in Example 4. Activation of the acid groupwith bis-imidazole-carbonyl leads to compound XXVIII (Eils et al,Synthesis, 1999, 275-81). The reaction with ethyl malonic acid affordsXXIX. Cyclization with hydroxylamine provides the hydroxy protectediso-oxazole XXX. The deprotection of the hydroxy functionality arrivesat the desired compound XXXI. (Frolund et al, J. Med. Chem., 2002, 45,2454-2468)

Method 2:

The hydroxyiso-oxazole compound XXXI can be derived in 4 steps. Thefirst step involves direct coupling of the 3-unsubstituted indole V witha protected hydroxy iso-oxazole methyl halogen (chloride or bromide)with a base (e.g. sodium hydroxide) in an alcohol solvent (e.g.methanol) system. (Sholtz et al, Chem. Ber., 1913, 46, 2145) Subsequentremoval of the methoxy group under reductive conditions and deprotectionof the protection group and protection of the indole nitrogenleads tothe desired compound XXXI. (Oster, T. A., et al, J. Org. Chem. 1983, 48,2454-68)

Method 3:

An alternative synthetic approach to compound XXXI, starts with compoundXXVII (prepared through reduction of 3-acetic acid) to generate thehydroxy imine XXXIV. Chlorination of XXXIV with chlorination reagents(e.g. NCS) arrive at intermediate XXXV. From the hydroxy iminiumchloride, a cyclization with acetylene would afford the protectedhydroxy iso-oxazole. The deprotection would provide the desired compoundXXXI. (Weidner-Wells, M. A. et al, Bioorg. & Med. Chem. Lett., 2004, 14,3069-72)

Acyl Cyanamide:

Compound XXXVIII can be prepared through a two step process startingfrom either Ia or Ib.

Step 1

The carboxylic acid group in Ia or Ib can be converted to acyl halideXXXVII through the use of reagents (e.g. thionyl chloride, phosphorouspentachloride, or phosphorous trichloride) in an inert solvent (e.g.dichloromethane). (Cao, J. et al, J. Med. Chem., 2003, 46, 2589-98 andKitamura, M. et al, Synthesis, 2003, 2415-26)

Step 2

The acyl cyanamide functionality can be introduced via coupling of thecyanamide with compound XXXVII to yield the desired product XXXVIII.(Belletire, J. L. et al, Syn. Commun., 1988, 18, 2063-72)

Sulfonamides:

The sulfonamide bio-isostere for carboxylic acid can be prepared in 6steps from from indolyl-3-acetic acid or propionic acid (if the linkeris to be extended)

Steps 1&2

Compound XXVII can be transformed to the corresponding alcohol XXXIXthrough treatment with reducing reagent such as lithium aluminum hydridein an inert solvent such as THF. The corresponding alcohol can beconverted to mesylate or halogen with the proper reagents such asmethane sulfonyl chloride or Phosphorous tribromide respectively.

Step 3

Intermediate XL can be prepared by treating XXXIX with sodium hydrogensulfide, hexabutyldistannathian, or1-(2-hydroxyethyl)-4,6-diphenylpyridine-2-thione to get to theethanethiol or propanethiol. (Gingras et al, Tet. Lett. 1990, 31,1397-1400, Maercker et al, Justus Liebigs Ann. Chem., 1865, 136, 88, orMolina et al, Tetrahedron Lett., 1985, 26 469-472.)

Step 4

The thiol XL can be oxidized to the corresponding sulfonic acid withoxidative reagents such as hydrogen peroxide to afford intermediate XLI.

Step 5

Compound XL can be treated to reagents (e.g. thionyl chloride orphosphorous pentachloride) to convert the sulfonic acid to thecorresponding sulfonyl chloride to arrive at intermediate XLII. (Scheme20, step 1)

Step 6

Sulfonamide isosteres of the carboxylic acid is then generated throughcoupling of the sulfonyl chloride XLIIIa with amine reagents (e.g.sodium amide or methylamine).

Acetyl-Sulfonamides:

Acetyl-sulfonamides XLIV can be prepared through the sulfonyl chlorideXLII in two steps.

Step 1

Compound XLII is treated to ammonia or sodium amide to yield XLIIIb.

Step 2

Compound XXXIIIb is then deprotonated and treated to acetic anhydride toarrive at the acetyl-sulfonamide XLIV.

Exemplary General Synthesis of Compounds of Formula L, where W, Y, and Zare Independently N or CH; n=0, 1, or 2.

Step 1: Preparation of Intermediate XLVII

Commerically available 4-hydroxy benzenesulfonic acid XLV, can bereacted with aryl halides, e.g., iodobenzene benzyl bromide etc., underBuckwald reaction conditions and SN₂ reaction conditions respectively,or with alcohols, e.g. benzyl alcohols under Mitsunobu reactionconditions, or other coupling reactions to afford XLVII.

Step 2: Preparation of Intermediate XLVIII

Compound of formula XLVII can be converted to the corresponding sulfonylchloride with reagents such as PCl₃, PCl₅, POCl₃, or SOCl₂.

Compound of formula L can be prepared by reacting the sulfonyl chlorideXLVIII with 5-methoxy-indole-3-propionic ester in presence of a base,e.g. aq. Potassium hydroxide, in THF.

Example 116 Synthesis of3-{5-Methoxy-1-[4-(pyridin-3-yloxy)-benzenesulfonyl]-1H-indol-3-yl}-propionicacid 143

Compound 143 can be prepared through methods described in Scheme 23,using 4-hydroxybenzenesulfonic acid and 3-hydroxypyridine to prepare thecorresponding sulfonyl chloride. The various coupling of the sulfonylchloride to 5-methoxy-indole-3-p;ropionic ester or the correspondingacid as described in Scheme 7, 10, or 12.

Example 117 Synthesis of3-{5-Methoxy-1-[4-(pyridin-4-yloxy)-benzenesulfonyl]-1H-indol-3-yl}-propionicacid 144

Compound 144 can be prepared through methods described in Scheme 23,using 4-hydroxybenzenesulfonic acid and 4-hydroxypyridine to prepare thecorresponding sulfonyl chloride. The various coupling of the sulfonylchloride to 5-methoxy-indole-3-p;ropionic ester or the correspondingacid as described in Scheme 7, 10, or 12.

Example 118 Synthesis of3-{5-Methoxy-1-[4-(pyridin-4-ylmethoxy)-benzenesulfonyl]-1H-indol-3-yl}-propionicacid 145

Compound 145 can be prepared through methods described in Scheme 23,using 4-hydroxybenzenesulfonic acid and 4-pyridylcarbinol to prepare thecorresponding sulfonyl chloride. The various coupling of the sulfonylchloride to 5-methoxy-indole-3-p;ropionic ester or the correspondingacid as described in Scheme 7, 10, or 12.

Example 119 Synthesis of3-[1-(3,5-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionicacid 146

Compound 146 can be prepared by reacting 5-methoxy-indole-3-p;ropionicester or the corresponding acid through methods with3,5-dichlorobenzenesulfonyl chloride as described in Scheme 7, 10, or12.

Example 120 Synthesis of3-[1-(3,5-Dimethoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionicacid 147

Compound 147 can be prepared by reacting 5-methoxy-indole-3-p;ropionicester or the corresponding acid through methods with3,5-dimethoxybenzenesulfonyl chloride as described in Scheme 7, 10, or12.

General Synthesis of Compounds of Formula LIV and LV

Step 1: Preparation of Intermediate LII

Compound LII can be prepared through coupling of indole (2 or 4) withsulfonyl chloride LI from methodologies described in Scheme 7 or 12.

Step 2: Preparation of Compound LIV or LV

Compound LIV or LV can be prepared through nucleophilic displacement ofthe bromomethyl group under basic conditions, in an inert solvent suchas DMF.

Example 121 Synthesis of3-{5-Methoxy-1-[4-(quinolin-7-ylaminomethyl)-benzenesulfonyl]-1H-indol-3-yl}-propionicacid 148

Compound 148 can be prepared via coupling of compound LII with thecorresponding Quinol-7-ylamine with the bromomethyl moiety in Scheme 24.

Example 122 Synthesis of3-{1-[4-(Isoquinolin-3-ylaminomethyl)-benzenesulfonyl]-5-methoxy-1H-indol-3-yl}-propionicacid 149

Compound 149 can be prepared via coupling of compound LII with thecorresponding isoquinolin-3-yl-amine with the bromomethyl moiety inScheme 24.

Example 123 Synthesis of3-{5-Methoxy-1-[4-(quinolin-6-ylaminomethyl)-benzenesulfonyl]-1H-indol-3-yl}-propionicacid 150

Compound 149 can be prepared via coupling of compound LII with thecorresponding quinolin-6-yl amine with the bromomethyl moiety in Scheme24.

Example 124 Synthesis of3-[5-Methoxy-1-(4-pyrrolo[2,3-b]pyridin-1-ylmethyl-benzenesulfonyl)-1H-indol-3-yl]-propionicacid 151

Compound 151 can be prepared via coupling of compound LII with thecorresponding 7-azaindole with the bromomethyl moiety in Scheme 24.

Example 125 Synthesis of3-[5-Methoxy-1-(4-phenoxymethyl-benzenesulfonyl)-1H-indol-3-yl]propionicacid 152

Compound 152 can be prepared via coupling of compound LII with thecorresponding phenol with the bromomethyl moiety in Scheme 24.

General Synthesis of Compounds of Formula LIX, LX, or LXI

Step 1: Preparation of Intermediate LVII

The intermediate LVII can be prepared through either similar methods asdescribed in step 1 of preparation of XLVII, or through nucleophilicdisplacement of a fluoro group.

Step 2: Preparation of Intermediate LVIII

The sulfonic acid can be converted to the corresponding sulfonylchloride with PCl₃, POCl₃, PCl₅, or SOCl₂.

Step 3: Preparation of Intermediate LIX

The sulfonyl chloride LVIII can be coupled to the indole intermediates 4to arrive at LIX.

Step 4: Preparation of Compound LX and LXI

The nitrile moiety can be further converted to either amide throughhydrolysis or amine through reduction.

Example 126 Synthesis of3-{5-Methoxy-1-[4-(pyridin-3-ylmethoxy)-benzenesulfonyl]-1H-indol-3-yl}-propionicacid 153

Compound 153 can be prepared through methods described in Scheme 23,using 4-hydroxybenzenesulfonic acid and 3-pyridinemethanol to preparethe corresponding sulfonyl chloride. The various coupling of thesulfonyl chloride to the indole-moiety are described in Scheme 7, 10, or12.

Example 127 Synthesis of3-{1-[4-(4-Aminomethyl-benzyloxy)-benzenesulfonyl]-5-methoxy-1H-indol-3-yl}-propionicacid 154

Compound 154 can be prepared through reduction of the nitrile group, asdescribed in Scheme 25. The nitrile functionality can be preparedthrough coupling of the sulfonyl chloride with the5-methoxyindole-3-propionic acid methyl ester. The sulfonyl chloride canbe prepared through coupling of the 4-hydroxy benzenesulfonic acid with4-cyanobenzyl bromide.

Example 128 Synthesis of3-{1-[4-(4-Carbamoyl-benzyloxy)-benzenesulfonyl]-5-methoxy-1H-indol-3-yl}-propionicacid 155

Compound 155 can be prepared through hydrolysis of the nitrile group, asdescribed in Scheme 25. The nitrile functionality can be preparedthrough coupling of the sulfonyl chloride with the5-methoxyindole-3-propionic acid methyl ester. The sulfonyl chloride canbe prepared through coupling of the 4-hydroxy benzenesulfonic acid with4-cyanobenzyl bromide.

Example 129 Synthesis of Compound 162

Step 1: Preparation of 5-Methoxy-1H-pyrrolo[3,2-b]pyridine 160

The title compound can be prepared through:

-   -   1. Reductive Cyclization with 158 (M. Mieczyslaw et. al, Liebigs        Ann. Chem. 1988, 203-208; D. Mazeas et. al, Heterocycles, 1999,        50, 1065-80.)    -   2. Reduction through catalytic hydrogenation and cyclization        under reflux conditions with        C-tert-butoxy-tetra-N-methyl-methanediamine 157 (K-H. Buchheit        et al, J. Med. Chem., 1995, 2331-2338).    -   3. Reductive cyclization with 159 (S. A. Filla et al, J. Med.        Chem., 2003, 46, 3060-71)

Step 2: Preparation of5-Methoxy-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde 161

The intermediate 161 can be prepared either through Vilsmeier reaction(K-H. Buchheit et al, J. Med. Chem., 1995, 2331-2338) or with1,3,5,7-tetraaza-adamantane (D. Mazeas et. al, Heterocycles, 1999, 50,1065-80).

The subsequent conversion to introduce the propionic acid side chain andthe sulfonamide can be achieve using methodologies as described inScheme 7 or 12.

Example 130 Synthesis of Compound 166

Step 1: Preparation of intermediate 164,5-Methoxy-1H-pyrrolo[2,3-c]pyridine

5-Methoxy-1H-pyrrolo[2,3-c]pyridine 164 can be prepared throughcyclization of 6-methoxy-4-trimethylsilanylethylnyl-pyridin-3-ylamine163 with cuprous iodide in DMF (D. Mazeas et. al, Heterocycles, 1999,50, 1065-80).

Step 2: Preparation of intermediate 165,5-Methoxy-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde

5-Methoxy-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde can be prepared from165 using with 1,3,5,7-tetraaza-adamantane under refluxing conditionswith DMF (D. Mazeas et. al, Heterocycles, 1999, 50, 1065-80).

The subsequent conversion to introduce the propionic acid side chain andthe sulfonamide can be achieve using methodologies as described inScheme 7 or 12.

Example 131 Synthesis of Compound 172

Step 1: Preparation of 168,6-Chloro-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine

1,2,3,5-Tetrahydro-pyrrolo[3,2-c]pyridin-6-one 167 can be converted tothe 6-Chloro-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine 168 with Phosphorousoxychloride (N. N. Bychikhina et. al, Chem. Heterocycl. Compds., 1982,18, 356-360)

Step 2: Preparation of 169,6-Methoxy-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine

6-Methoxy-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine 169 can be preparedthrough direct displacement of the chloro group in 168 with sodiummethoxide. (V. A. Azimov et. al, Chem. Heterocycl. Compd. 1981, 17,1648-1653)

Step 3: Preparation of 170, 6-Methoxy-1H-pyrrolo[3,2-c]pyridine

6-Methoxy-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine 169 is oxidized to thecorresponding 170 with the use of MnO₂. (V. A. Azimov et. al, Chem.Heterocycl. Compd. 1981, 17, 1648-1653)

Step 4: Preparation of 171,6-Methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbaldehyde

6-Methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbaldehyde is prepared throughVilsmeier conditions with 170. (N. N. Bychikhina et. al, Chem.Heterocycl. Compds., 1982, 18, 356-360)

The subsequent conversion to introduce the propionic acid side chain andthe sulfonamide can be achieve using methodologies as described inScheme 7 or 12.

Example 132 Synthesis of Compound 181

Step 1: Preparation of 175

2-chloro-7H-pyrrolo[2,3-d]pyrimidine 175 can be prepared from either2-chloro-5-(2-ethoxy-vinyl)-pyrimidin-4-ylamine 173 or2-chloro-5-(2,2-dimethoxy-ethyl)-pyrimidin-4-ylamine 174 (under refluxconditions in methanol with concentrated hydrochloric acid (M. Cheung etal, Tet. Lett., 2001, 42, 999-1002).

Step 2: Preparation of 176

The 2-chloro group in 2-chloro-7H-pyrrolo[2,3-d]pyrimidine 176 can beconverted to the corresponding methoxy moiety 176 through nucleophilicdisplacement of the chloro group by sodium methoxide (F., Seela et. al,Liebigs Ann. Chem. 1985, 312-320.)

Step 3: Preparation of 177

Intermediate 177 can be prepared from 176 through iodination of 176 withIodine, with base in N,N-dimethylformamide at ambient temperature. (T.,Sakamoto, Takao et. al, J. Chem. Soc. Perkin Trans. 1, 1996; 459-464)

Step 4: Preparation of 178

Protection of the pyrrolopyrimidine 177 with 4-methoxybenzenesulfonylchloride can be achieve through a bi-phasic coupling using aqueoussodium hydroxide solution or with sodium hydride in DMF.

Step 5: Preparation of 179

The 3-carboxylic acid functionality can be prepared throughdeprotonation with a grignard reaction, follow by CO₂ addition andacidification to yield the desired intermediate from 177. (Y. Kondo, et.al Heterocycles, 1996, 42, 205-8.)

The subsequent conversion to introduce the propionic acid side chain andthe sulfonamide can be achieve using methodologies as described inScheme 9

Example 133 Synthesis of Compound 190

Step 1: Synthesis of Intermediate 184

Intermediate 184 can be prepared from 3-acetyl-2-chloropyridine, throughcyclization with methylhyrazine. (B. M. Lynch et. al, Canadian Journalof Chemistry, 1988, 66, 420-8)

Step 2: Synthesis of Intermediate 185

Intermediate 185 is prepared through nitration of the 5-position withnitric acid and sulfuric acid. (B. M. Lynch et. al, Canadian Journal ofChemistry, 1988, 66, 420-8)

Step 3: Synthesis of Intermediate 186

The nitro group is reduced the corresponding amine group through use ofreagents such as palladium on activated carbon. (B. M. Lynch et. al,Canadian Journal of Chemistry, 1988, 66, 420-8)

Step 4: Synthesis of Intermediate 187

The amine group is then converted to diazonium salt with sodium nitrateand concentrated hydrochloric acid. The diazonium ion is then quencedwith methanol to yield the corresponding methoxy functionality. (B. M.Lynch et. al, Canadian Journal of Chemistry, 1988, 66, 420-8)

Step 5: Synthesis of Intermediate 188

The 3-methyl group is oxidized through KMnO4 oxidation to the carboxylicacid. (B. M. Lynch et. al, Canadian Journal of Chemistry, 1988, 66,420-8)

The subsequent conversion to introduce the propionic acid side chain andthe sulfonamide can be achieve using methodologies as described inScheme 9 to arrive at the desired compound 190.

Example 134 Crystallization and Crystal Structures of PPARs

PPARα, PPARδ, and PPARγ have each been crystallized and crystalstructures determined and reported. Such structures and atomiccoordinates are available at Protein Data Bank (PDB) (available on theinternet on the Web where the remainder of the address following www isrcsb.org). For PPARα deposited atomic coordinates are available underPDB code 1KKQ, Xu, 2001, Nature 415, p 813; for PPARδ under code 1GWX,Xu, 1999, Mol Cell, 3, p 397; and for PPARγ under code 1PRG, Notle, etal, 1998, Nature, 395, p 137. (Each of the references cited inconnection with PPAR structures is hereby incorporated by reference inits entirety.) Additional atomic coordinate deposits are available,where PDB codes of the deposited structures are: 1K7L, 1I7G, and 1KKQfor PPARalpha, 1PRG, 2PRG, 3PRG, 4PRG, 1K74, 1FM6, 1FM9, 1171, and 1KNUfor PPARgamma, 1GWX, 2GWX, and 3GWX for PPARdelta.

In addition, high quality crystals of the PPARs can be obtained bycrystallization under conditions as described below. The structures canthen be readily obtained by using published structures as references.Sequences encoding the individual PPARs can be readily obtained.Sequences encoding the individual PPARs were obtained from the NCBILocusLink (on the Web where the remainder of the address following wwwis ncbi.nih.gov/LocusLink). The sequence accession numbers are:NM_(—)005036 (cDNA sequence for PPARa), NP_(—)005027 (protein sequencefor PPARa), NM_(—)015869 (cDNA sequence for PPARg isoform 2),NP_(—)056953 (protein sequence for PPARg isoform 2), NM_(—)006238 (cDNAsequence for PPARd), and NP_(—)006229 (protein sequence for PPARd).Using these sequences, the coding sequences can be isolated from a cDNAlibrary using conventional cloning techniques. PPAR proteins can then beexpressed and purified by conventional methods.

In the present case, PPAR polypeptides were obtained by PCR from a cDNAlibrary (Invitrogen), and sub-cloned to obtain constructs forexpression. Expressing those sequences thus provided PPAR polypeptidesfor crystallization.

In addition to the conditions published for crystallizing each of thePPARs, the following crystallization conditions have been used forproducing co-crystals of each of the PPAR ligand binding domains withcompounds of Formula I. The particular ligand binding domain sequenceused for PPARalpha: GenBank accession: NP_(—)005027 (protein sequence)and NM_(—)005036 (mRNA sequence), ligand binding domain: amino acidresidues 196-468.

For PPARgamma the ligand binding domain used corresponded to amino acidresidues 174_(—)475 of GenBank accession: NP_(—)005028 (proteinsequence) and NM_(—)005037 (mRNA sequence).

For PPARdelta the ligand binding domain used corresponded to amino acid165-441 of GenBank accession: NP_(—)006229 (protein sequence) andNM_(—)006238 (mRNA sequence).

Exemplary Crystallization conditions for PPARgamma:

1. with 2× molar excess of SRC-1 and 1 mM compound

-   -   0.2M Ammonium Acetate, 0.1M Bistris, pH 6.5, 13-25% PEG4k, or    -   0.2M Ammonium Acetate, 0.1M Hepes, pH 7.5, 13-25% PEG4k

2. with 0.3-1 mM compound

-   -   12-22% PEG 8k, 0.2M NaAcetate, 0.1M Hepes pH 7.5; or    -   0.6M-1.0M NaCltrate, 0.1M Hepes pH 7.5; or    -   0.9-1.4M Ammonium Sulfate, 0.1M Hepes pH 7.5

Crystallization conditions for PPARalpha:

1. with 2× molar excess of SRC-1 and 1 mM compound

-   -   9-30% PEG 4K, 0.2M Ammonium Acetate, 0.1M Citrate, pH 5.6; or    -   17-30% PEG4k, 0.2M Lithium Sulfate, 0.1M Tris/HCl, pH 8.5; or    -   22-30% PEG4k, 0.2M NaAcetate, 0.1M Tris/HCl, pH 8.5

2. with co-concentrated compound

-   -   0.6-1.0M Lithium Sulfate, 0.1M Tris/HCl pH 8.5

Crystallization conditions for PPARdelta:

1. with 2× molar excess of SRC-1 and co-concentrated compound

-   -   0.2-1.2M KNaTartrate, 2.5% 1,2 Propanediol, 0.1M Mes pH 5.5-6.5

The X-ray diffraction data from such co-crystals were then collectedfrom synchrotron radiation facilities. The useable diffraction data wereof high resolution such as 1.9A-3.0A, preferably 2.5A or higher, morepreferably 2.2A or higher, most preferably 2.0A or higher. The3-dimensional structures of proteins were determined with the co-crystaldiffraction data by molecular replacement method using the publishedstructures as starting search model. The molecular replacement solutionsof the protein structures were then refined and used for calculatingdifference Fourier maps. The difference Fourier maps provide basis forthe determination of compound binding geometry. The compound orientationand structure within the protein ligand binding site were determinedbased on the information obtained from the co-crystal diffraction data.A skilled person in this art will be able to interpret the X-raydiffraction data according to the compound structures which wereinvolved in the co-rystallization experiments. Water molecules that aretightly bound to the proteins are an integral part of the proteinstructures. They can also be critical mediators of protein ligandinteractions. Such water molecules are termed “structural water”. Thestructural water molecules are built into the structure model based ondifference Fourier maps through the iterative refinement process. Thecompound-protein complex structures including structural water moleculeswere refined against the co-crystal diffraction data using computationalcrystallography methods in an iterative manner to yield accurate atomiccoordinates for further ligand design process.

Example 135 Exemplary Compounds of Formula I

The structures, IUPAC names, and molecular weights for synthesizedexemplary compounds of Structure I are shown below in Table 1.

TABLE 1 Number Structure M. Wt IUPAC name 28

189.2 3-(1H-Indol-3-yl)-propionic acid 96

219.2 3-(5-Methoxy-1H-indol-3-yl)- propionic acid 4

233.3 3-(5-Methoxy-1H-indol-3-yl)- propionic acid methyl ester 29

359.4 3-(1-Benzenesulfonyl-5-methoxy- 1H-indol-3-yl)-propionic acid 30

339.4 3-[5-Methoxy-1-(3-methoxy- benzyl)-1H-indol-3-yl]-propionic acid31

343.8 3-[1-(3-Chloro-benzyl)-5-methoxy- 1H-indol-3-yl]-propionic acid 32

327.3 3-[1-(4-Fluoro-benzyl)-5-methoxy- 1H-indol-3-yl]-propionic acid 33

343.8 3-[1-(4-Chloro-benzyl)-5-methoxy- 1H-indol-3-yl]-propionic acid 34

339.4 3-[5-Methoxy-1-(2-methoxy- benzyl)-1H-indol-3-yl]-propionic acid35

393.4 3-[5-Methoxy-1-(2- trifluoromethoxy-benzyl)-1H-indol-3-yl]-propionic acid 36

393.4 3-[5-Methoxy-1-(3- trifluoromethoxy-benzyl)-1H-indol-3-yl]-propionic acid 37

306.4 3-(1-Ethylthiocarbamoyl-5- methoxy-1H-indol-3-yl)-propionic acid38

373.4 3-[5-Methoxy-1-(toluene-4- sulfonyl)-1H-indol-3-yl]-propionic acid97

329.4 3-(1-Benzenesulfonyl-1H-indol-3- yl)-propionic acid 41

401.5 3-[1-(4-Isopropyl- benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 40

415.5 3-[1-(4-Isopropyl- benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 43

431.5 3-[1-(4-Butoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 42

445.5 3-[1-(4-Butoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 45

443.4 3-[5-Methoxy-1-(4- trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid 44

457.4 3-[5-Methoxy-1-(4- trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester 47

451.5 3-[5-Methoxy-1-(4-phenoxy- benzenesulfonyl)-1H-indol-3-yl]-propionic acid 46

465.5 3-[5-Methoxy-1-(4-phenoxy- benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester 49

393.8 3-[1-(4-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 48

407.9 3-[1-(4-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 50

398.4 3-[1-(4-Cyano-benzenesulfonyl)-5- methoxy-1H-indol-3-yl]-propionicacid methyl ester 52

442.3 3-[1-(3,4-Dichloro- benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 5

403.4 3-[5-Methoxy-1-(4-methoxy- benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester 54

441.4 3-[5-Methoxy-1-(4-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]- propionic acid methyl ester 56

391.4 3-[1-(4-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 72

379.4 3-[5-Methoxy-1-(thiophene-2- sulfonyl)-1H-indol-3-yl]-propionicacid methyl ester 73

365.4 3-[5-Methoxy-1-(thiophene-2- sulfonyl)-1H-indol-3-yl]-propionicacid 74

368.4 3-(5-Methoxy-1- phenylthiocarbamoyl-1H-indol-3- yl)-propionic acidmethyl ester 75

354.4 3-(5-Methoxy-1- phenylthiocarbamoyl-1H-indol-3- yl)-propionic acid58

465.5 3-[5-Methoxy-1-(3-phenoxy- benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester 60

391.4 3-[1-(3-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 62

387.4 3-[5-Methoxy-1-(toluene-3- sulfonyl)-1H-indol-3-yl]-propionic acidmethyl ester 64

407.9 3-[1-(3-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methy ester 66

403.4 3-[5-Methoxy-1-(3-methoxy- benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester 68

441.4 3-[5-Methoxy-1-(3-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]- propionic acid methyl ester 51

384.4 3-[1-(4-Cyano-benzenesulfonyl)-5- methoxy-1H-indol-3-yl]-propionicacid 53

428.3 3-[1-(3,4-Dichloro- benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 1

389.4 3-[5-Methoxy-1-(4-methoxy- benzenesulfonyl)-1H-indol-3-yl]-propionic acid 55

427.4 3-[5-Methoxy-1-(4-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]- propionic acid 57

377.4 3-[1-(4-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 98

373.4 3-(1-Benzenesulfonyl-5-methoxy- 1H-indol-3-yl)-propionic acidmethyl ester 71

309.4 3-(1-Benzyl-5-methoxy-1H-indol- 3-yl)-propionic acid 70

323.4 3-(1-Benzyl-5-methoxy-1H-indol- 3-yl)-propionic acid methyl ester59

451.5 3-[5-Methoxy-1-(3-phenoxy- benzenesulfonyl)-1H-indol-3-yl]-propionic acid 61

377.4 3-[1-(3-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 63

373.4 3-[5-Methoxy-1-(toluene-3- sulfonyl)-1H-indol-3-yl]-propionic acid65

393.8 3-[1-(3-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 67

389.4 3-[5-Methoxy-1-(3-methoxy- benzenesulfonyl)-1H-indol-3-yl]-propionic acid 69

427.4 3-[5-Methoxy-1-(3-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]- propionic acid 90

408.3 3-(1-Benzenesulfonyl-5-bromo-1H- indol-3-yl)-propionic acid 79

443.4 3-[5-Methoxy-1-(3- trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid 78

457.4 3-[5-Methoxy-1-(3- trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester 77

415.5 3-[1-(4-Butyl-benzenesulfonyl)-5- methoxy-1H-indol-3-yl]-propionicacid 76

429.5 3-[1-(4-Butyl-benzenesulfonyl)-5- methoxy-1H-indol-3-yl]-propionicacid methyl ester 91

425.5 3-(1-Benzenesulfonyl-5-thiophen- 3-yl-1H-indol-3-yl)-propionicacid methyl ester 93

419.5 3-(1-Benzenesulfonyl-5-phenyl-1H- indol-3-yl)-propionic acidmethyl ester 80

337.4 3-(1-Benzoyl-5-methoxy-1H-indol- 3-yl)-propionic acid methyl ester81

323.3 3-(1-Benzoyl-5-methoxy-1H-indol- 3-yl)-propionic acid 92

411.5 3-(1-Benzenesulfonyl-5-thiophen- 3-yl-1H-indol-3-yl)-propionicacid 94

405.5 3-(1-Benzenesulfonyl-5-phenyl-1H- indol-3-yl)-propionic acid 82

373.4 3-(1-Benzenesulfonyl-5-ethoxy-1H- indol-3-yl)-propionic acid 83

417.5 3-[1-(4-Isopropoxy- benzenesulfonyl)-5- methoxy-1H-indol-3-yl]-propionic acid 84

352.4 3-(5-Methoxy-1-phenylcarbamoyl- 1H-indol-3-yl)- propionic acidmethyl ester 86

387.5 3-[1-(4-Ethyl-benzenesulfonyl)-5- methoxy-1H-indol-3-yl]-propionicacid 85

338.4 3-(5-Methoxy-1-phenylcarbamoyl- 1H-indol-3-yl)-propionic acid 6

357.4 3-(1-Benzenesulfonyl-5-ethyl-1H- indol-3-yl)-propionic acid 22

387.5 3-(1-Benzenesulfonyl-5- isopropoxy-1H-indol-3-yl)- propionic acid99

365.4 3-[5-Methoxy-1-(thiophene-3- sulfonyl)- 1H-indol-3-yl]-propionicacid 16

190.2 Indazole-3-propionic acid 39

330.4 3-(1-Benzenesulfonyl-1H-indazol- 3-yl)-propionic acid 95

190.2 3-(1H-Pyrrolo[3,4-b]pyridin-3-yl)-pro- pionic acid 101

419.5 3-[1-(3,4-Dimethoxy- benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 102

396.4 3-[1-(3,4-Difluoro- benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 103

407.8 3-[1-(3-chloro-4-methyl- benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 104

347.5 3-[1-(benzenesulfonyl)-5-fluoro- 1H-indol-3-yl]-propionic acid 105

323.2 3-[1-(benzenesulfonyl)-5-methyl- 1H-indol-3-yl]-propionic acid 106

363.7 3-[1-(benzenesulfonyl)-5-chloro- 1H-indol-3-yl]-propionic acid 107

391.3 3-[1-(3-fluoro-4-methyl- benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 108

401.2 3-[1-(2,3-Dihydro-benzofuran-5- sulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 109

401.5 3-[1-(4-ethyl-benzenesulfonyl)-5- ethoxy-1H-indol-3-yl]-propionicacid 110

403.6 3-[1-(4-methoxy-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid 111

3-[1-(3-trifluoromethoxy- benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid 112

429.4 3-[1-(4-butyl-benzenesulfonyl)-5- ethoxy-1H-indol-3-yl]-propionicacid 113

445.5 3-[1-(4-butoxy-benzenesulfonyl)-5- ethoxy-1H-indol-3-yl]-propionicacid 114

442.2 3-[1-(3,4-dichloro- benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid 115

403.5 3-[1-(3-methoxy-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid 116

465.3 3-[1-(4-phenoxy-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid 143

452.58 3-{5-Methoxy-1-[4-(pyridin-3- yloxy)-benzenesulfonyl]-1H-indol-3-yl}-propionic acid 144

452.58 3-{5-Methoxy-1-[4-(pyridin-4- yloxy)-benzenesulfonyl]-1H-indol-3-yl}-propionic acid 145

466.51 3-{5-Methoxy-1-[4-(pyridin-4- ylmethoxy)-benzenesulfonyl]-1H-indol-3-yl}-propionic acid 146

428.29 3-[1-(3,5-Dichloro- benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 147

419.45 3-[1-(3,5-Dimethoxy- benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 148

515.58 3-{5-Methoxy-1-[4-(quinolin-7- ylaminomethyl)-benzenesulfonyl]-1H-indol-3-yl}-propionic acid 149

515.58 3-{1-[4-(Isoquinolin-3- ylaminomethyl)-benzenesulfonyl]-5-methoxy-1H-indol-3-yl}- propionic acid 150

515.58 3-{5-Methoxy-1-[4-(quinolin-6- ylaminomethyl)-benzenesulfonyl]-1H-indol-3-yl}-propionic acid 151

489.54 3-[5-Methoxy-1-(4-pyrrolo[2,3- b]pyridin-1-ylmethyl-benzenesulfonyl)-1H-indol-3-yl]- propionic acid 152

465.53 3-[5-Methoxy-1-(4- phenoxymethyl-benzenesulfonyl)-1H-indol-3-yl]propionic acid 153

466.51 3-{5-Methoxy-1-[4-(pyridin-3- ylmethoxy)-benzenesulfonyl]-1H-indol-3-yl}-propionic acid 154

494.57 3-{1-[4-(4-Aminomethyl- benzyloxy)-benzenesulfonyl]-5-methoxy-1H-indol-3-yl}-propionic acid 155

508.55 3-{1-[4-(4-Carbamoyl-benzyloxy)- benzenesulfonyl]-5-methoxy-1H-indol-3-yl}-propionic acid

Agonist activities for exemplary compounds from Table 1 were determined,and are shown in Table 2, where “+” indicates activity 10 μM, and “−”indicates >10 μM. These activities were determined as described inExample 1.

TABLE 2 PPARα agonist PPARδ Agonist PPARγ Agonist Compound # (μM) (μM)(μM) 29 + + + 97 − − − 39 − − − 43 + + + 49 + + + 75 − − − 53 + + + 71 +− − 79 + + + 77 + + + 81 + − − 92 + − + 82 + + + 85 − − − 6 − − +

TABLE 3 MOLSTRUCTURE molecular weight MOLNAME

251.284 5-BENZYLOXYINDOLE-3- CARBOXALDEHYDE

159.187 4-METHYLINDOLE-3-ALDEHYDE

159.187 6-METHYLINDOLE-3- CARBOXALDEHYDE

251.284 7-BENZYLOXYINDOLE-3- CARBOXALDEHYDE

251.284 6-BENZYLOXYINDOLE-3- CARBOXALDEHYDE

179.605 2-CHLORO-1H-INDOLE-3- CARBALDEHYDE

251.284 4-BENZYLOXYINDOLE-3- CARBOXALDEHYDE

203.196 3-FORMYLINDOLE-5- CARBOXYLIC ACID METHYL ESTER

203.196 METHYL 3-FORMYLINDOLE-6- CARBOXYLATE

204.184 3-FORMYL-2-METHYL-5- NITROINDOLE

189.169 3-FORMYL-1H-INDOLE-7- CARBOXYLIC ACID

231.25 TIMTEC-BB ST002282

190.157 7-NITROINDOLE-2- CARBOXALDEHYDE

190.157 5-NITROINDOLE-3- CARBOXALDEHYDE

170.17 5-CYANOINDOLE-3-ALDEHYDE

249.268 6-BENZOYL-1H-INDOLE-3- CARBOXALDEHYDE

249.268 5-BENZOYL-1H-INDOLE-3- CARBOXALDEHYDE

173.214 7-ETHYL-1H-INDOLE-3- CARBOXALDEHYDE

196.636 5-AMINO-1H-INDOLE-3- CARBOXALDEHYDE HYDROCHLORIDE

207.252 5-METHYLSULPHINYLINDOLE-3- CARBOXALDEHYDE

163.15 7-FLUOROINDOLE-3- CARBOXALDEHYDE

191.145 6-NITRO-1H-INDAZOLE-3- CARBALDEHYDE

204.184 METHYL-3-AL-4-INDAZOLE CARBOXYLATE

151.595 6-CHLOROINDOLE

131.177 6-METHYLINDOLE

162.147 7-NITROINDOLE

142.16 6-CYANOINDOLE

177.202 5,7-DIMETHOXY INDOLE

147.176 6-METHOXYINDOLE

253.299 5-BENZYLOXY-6- METHOXYINDOLE

147.176 7-METHOXYINDOLE

162.147 6-NITROINDOLE

145.204 7-ETHYLINDOLE

163.175 5-HYDROXY-6-METHOXYINDOLE

175.186 METHYL INDOLE-5- CARBOXYLATE

175.186 METHYL INDOLE-6- CARBOXYLATE

175.186 METHYL INDOLE-7- CARBOXYLATE

273.334 N-(4- MORPHOLINOETHYL)INDOLE-6- CARBOXAMIDE

204.228 N-METHOXY-N-METHYL-INDOLE- 6-CARBOXAMIDE

159.187 5-ACETYLINDOLE

241.044 5-BROMO-7-NITROINDOLE

196.046 7-BROMOINDOLE

135.14 7-FLUOROINDOLE

174.202 5-ACETAMIDOINDOLE

151.595 7-CHLOROINDOLE

147.176 INDOLE-5-METHANOL

147.176 INDOLE-6-METHANOL

147.176 INDOLE-7-METHANOL

179.242 5-METHYLSULPHINYLINDOLE

179.242 6-METHYLSULPHINYLINDOLE

185.147 5-(TRIFLUOROMETHYL)INDOLE

191.257 N-(1H-INDOL-6-YL)THIOUREA

226.072 7-BROMO-5-METHOXYINDOLE

195.241 6-(METHYLSULFONYL)-1H- INDOLE

163.135 5-NITROINDAZOLE

163.135 6-NITROINDAZOLE

163.135 7-NITROINDAZOLE

183.213 ACB-BLOCKS PYR-0331

183.213 ACB-BLOCKS PYR-0332

206.272 N-(6-METHYL-1H-INDAZOL-5- YL)THIOUREA

192.245 N-(1H-INDAZOL-7-YL)THIOUREA

192.245 N-(1H-INDAZOL-6-YL)THIOUREA

197.035 6-BROMOINDAZOLE

190.201 ETHYL 1H-INDAZOLE-5- CARBOXYLATE

211.061 CBI-BB ZERO/005553

148.164 5-HYDROXYMETHYL-1H- INDAZOLE

Additional exemplary compounds of Formula I are described in Table 4.Table 4 describes exemplary compounds by specifying substituents foreach of the bicyclic cores shown in the Summary herein, except thatsubstituents on a nitrogen (N) in the 6-membered ring are excluded, andthe 6-membered ring includes at least one alkoxy or thioethersubstituent at the 5- or 6-position. Thus, for example, for a bicycliccore that includes a N at the 5-position, only those substitutentcombinations that do not have a substitutent at the 5-position and havean alkoxy or thioether at the 6-position apply to that bicylic core.Where no substituent is specified for a ring position, it is to beunderstood that there is no substituent if the ring atom at thatposition is a N, and as H if the ring atom at that position is a carbon(C). All compounds include a —CH₂CH₂— linker at the 3-position; thespecification of the 3-substituent in Table 4 is thus the moietyattached to that linker.

The numbering of the ring atoms as referenced herein, including in Table4, is shown in the following structure. This structure includes theindolyl ring structure, but as used herein, the numbering for the otherbicyclic structures using the same numbering for corresponding atoms. Inaddition, this structure shows the 1-position substituents referenced inTable 4, where L is a linker group attached to the bicyclic core, Ar isan aromatic group (i.e., aryl or heteroaryl), and A refers to asubstituent or substituents on that aromatic group.

TABLE 4 1 L¹ Ar A 3 5 6 SO₂ phenyl COOH methoxy SO₂ phenyl CF₃ COOHmethoxy SO₂ phenyl CH₂CF₃ COOH methoxy SO₂ phenyl Halo substituted alkylCOOH methoxy SO₂ phenyl OCH₃ COOH methoxy SO₂ phenyl OCH₂CH₃ COOHmethoxy SO₂ phenyl OCH₂CH₂CH₃ COOH methoxy SO₂ phenyl OCH₂CH₂CH₂CH₃ COOHmethoxy SO₂ phenyl OCH₂CH₂CH₂CH₂CH₃ COOH methoxy SO₂ phenyl C5-C8 alkoxyCOOH methoxy SO₂ phenyl Halo substituted alkoxy COOH methoxy SO₂ phenylCH₃ COOH methoxy SO₂ phenyl CH₂CH₃ COOH methoxy SO₂ phenyl CH₂CH₂CH₃COOH methoxy SO₂ phenyl CH₂CH₂CH₂CH₃ COOH methoxy SO₂ phenyl C5-C8 alkylCOOH methoxy SO₂ phenyl F COOH methoxy SO₂ phenyl F,F COOH methoxy SO₂phenyl F,Cl COOH methoxy SO₂ phenyl Cl COOH methoxy SO₂ phenyl Cl,ClCOOH methoxy SO₂ phenyl -(1 to 4 linearly linked COOH methoxy atomlinker)-optionally subst. aryl SO₂ phenyl -(1 to 4 linearly linked COOHmethoxy atom linker)-optionally subst. heteroaryl SO₂ pyridinyl COOHmethoxy SO₂ Pyridinyl CF₃ COOH methoxy SO₂ Pyridinyl CH₂CF₃ COOH methoxySO₂ Pyridinyl Halo substituted alkyl COOH methoxy SO₂ Pyridinyl OCH₃COOH methoxy SO₂ Pyridinyl OCH₂CH₃ COOH methoxy SO₂ Pyridinyl OCH₂CH₂CH₃COOH methoxy SO₂ Pyridinyl OCH₂CH₂CH₂CH₃ COOH methoxy SO₂ PyridinylOCH₂CH₂CH₂CH₂CH₃ COOH methoxy SO₂ Pyridinyl C5-C8 alkoxy COOH methoxySO₂ Pyridinyl Halo substituted alkoxy COOH methoxy SO₂ Pyridinyl CH₃COOH methoxy SO₂ Pyridinyl CH₂CH₃ COOH methoxy SO₂ Pyridinyl CH₂CH₂CH₃COOH methoxy SO₂ Pyridinyl CH₂CH₂CH₂CH₃ COOH methoxy SO₂ Pyridinyl C5-C8alkyl COOH methoxy SO₂ Pyridinyl F COOH methoxy SO₂ Pyridinyl F,F COOHmethoxy SO₂ Pyridinyl F,Cl COOH methoxy SO₂ Pyridinyl Cl COOH methoxySO₂ Pyridinyl Cl,Cl COOH methoxy SO₂ Pyridinyl -(1 to 4 linearly linkedCOOH methoxy atom linker)-optionally subst. aryl SO₂ Pyridinyl -(1 to 4linearly linked COOH methoxy atom linker)-optionally subst. heteroarylCO Phenyl COOH methoxy CO Phenyl CF₃ COOH methoxy CO Phenyl CH₂CF₃ COOHmethoxy CO Phenyl Halo substituted alkyl COOH methoxy CO Phenyl OCH₃COOH methoxy CO Phenyl OCH₂CH₃ COOH methoxy CO Phenyl OCH₂CH₂CH₃ COOHmethoxy CO Phenyl OCH₂CH₂CH₂CH₃ COOH methoxy CO Phenyl OCH₂CH₂CH₂CH₂CH₃COOH methoxy CO Phenyl C5-C8 alkoxy COOH methoxy CO Phenyl Halosubstituted alkoxy COOH methoxy CO Phenyl CH₃ COOH methoxy CO PhenylCH₂CH₃ COOH methoxy CO Phenyl CH₂CH₂CH₃ COOH methoxy CO PhenylCH₂CH₂CH₂CH₃ COOH methoxy CO Phenyl C5-C8 alkyl COOH methoxy CO Phenyl FCOOH methoxy CO Phenyl F,F COOH methoxy CO Phenyl F,Cl COOH methoxy COPhenyl Cl COOH methoxy CO Phenyl Cl,Cl COOH methoxy CO Phenyl -(1 to 4linearly linked COOH methoxy atom linker)-optionally subst. aryl COPhenyl -(1 to 4 linearly linked COOH methoxy atom linker)-optionallysubst. heteroaryl CO pyridinyl COOH methoxy CO Pyridinyl CF₃ COOHmethoxy CO Pyridinyl CH₂CF₃ COOH methoxy CO Pyridinyl Halo substitutedalkyl COOH methoxy CO Pyridinyl OCH₃ COOH methoxy CO Pyridinyl OCH₂CH₃COOH methoxy CO Pyridinyl OCH₂CH₂CH₃ COOH methoxy CO PyridinylOCH₂CH₂CH₂CH₃ COOH methoxy CO Pyridinyl OCH₂CH₂CH₂CH₂CH₃ COOH methoxy COPyridinyl C5-C8 alkoxy COOH methoxy CO Pyridinyl Halo substituted alkoxyCOOH methoxy CO Pyridinyl CH₃ COOH methoxy CO Pyridinyl CH₂CH₃ COOHmethoxy CO Pyridinyl CH₂CH₂CH₃ COOH methoxy CO Pyridinyl CH₂CH₂CH₂CH₃COOH methoxy CO Pyridinyl C5-C8 alkyl COOH methoxy CO Pyridinyl F COOHmethoxy CO Pyridinyl F,F COOH methoxy CO Pyridinyl F,Cl COOH methoxy COPyridinyl Cl COOH methoxy CO Pyridinyl Cl,Cl COOH methoxy CO Pyridinyl-(1 to 4 linearly linked COOH methoxy atom linker)-optionally subst.aryl CO Pyridinyl -(1 to 4 linearly linked COOH methoxy atomlinker)-optionally subst. heteroaryl SO₂ phenyl COOH ethoxy SO₂ phenylCF₃ COOH ethoxy SO₂ phenyl CH₂CF₃ COOH ethoxy SO₂ phenyl Halosubstituted alkyl COOH ethoxy SO₂ phenyl OCH₃ COOH ethoxy SO₂ phenylOCH₂CH₃ COOH ethoxy SO₂ phenyl OCH₂CH₂CH₃ COOH ethoxy SO₂ phenylOCH₂CH₂CH₂CH₃ COOH ethoxy SO₂ phenyl OCH₂CH₂CH₂CH₂CH₃ COOH ethoxy SO₂phenyl C5-C8 alkoxy COOH ethoxy SO₂ phenyl Halo substituted alkoxy COOHethoxy SO₂ phenyl CH₃ COOH ethoxy SO₂ phenyl CH₂CH₃ COOH ethoxy SO₂phenyl CH₂CH₂CH₃ COOH ethoxy SO₂ phenyl CH₂CH₂CH₂CH₃ COOH ethoxy SO₂phenyl C5-C8 alkyl COOH ethoxy SO₂ phenyl F COOH ethoxy SO₂ phenyl F,FCOOH ethoxy SO₂ phenyl F,Cl COOH ethoxy SO₂ phenyl Cl COOH ethoxy SO₂phenyl Cl,Cl COOH ethoxy SO₂ phenyl -(1 to 4 linearly linked COOH ethoxyatom linker)-optionally subst. aryl SO₂ phenyl -(1 to 4 linearly linkedCOOH ethoxy atom linker)-optionally subst. heteroaryl SO₂ pyridinyl COOHethoxy SO₂ Pyridinyl CF₃ COOH ethoxy SO₂ Pyridinyl CH₂CF₃ COOH ethoxySO₂ Pyridinyl Halo substituted alkyl COOH ethoxy SO₂ Pyridinyl OCH₃ COOHethoxy SO₂ Pyridinyl OCH₂CH₃ COOH ethoxy SO₂ Pyridinyl OCH₂CH₂CH₃ COOHethoxy SO₂ Pyridinyl OCH₂CH₂CH₂CH₃ COOH ethoxy SO₂ PyridinylOCH₂CH₂CH₂CH₂CH₃ COOH ethoxy SO₂ Pyridinyl C5-C8 alkoxy COOH ethoxy SO₂Pyridinyl Halo substituted alkoxy COOH ethoxy SO₂ Pyridinyl CH₃ COOHethoxy SO₂ Pyridinyl CH₂CH₃ COOH ethoxy SO₂ Pyridinyl CH₂CH₂CH₃ COOHethoxy SO₂ Pyridinyl CH₂CH₂CH₂CH₃ COOH ethoxy SO₂ Pyridinyl C5-C8 alkylCOOH ethoxy SO₂ Pyridinyl F COOH ethoxy SO₂ Pyridinyl F,F COOH ethoxySO₂ Pyridinyl F,Cl COOH ethoxy SO₂ Pyridinyl Cl COOH ethoxy SO₂Pyridinyl Cl,Cl COOH ethoxy SO₂ Pyridinyl -(1 to 4 linearly linked COOHethoxy atom linker)-optionally subst. aryl SO₂ Pyridinyl -(1 to 4linearly linked COOH ethoxy atom linker)-optionally subst. heteroaryl COPhenyl COOH ethoxy CO Phenyl CF₃ COOH ethoxy CO Phenyl CH₂CF₃ COOHethoxy CO Phenyl Halo substituted alkyl COOH ethoxy CO Phenyl OCH₃ COOHethoxy CO Phenyl OCH₂CH₃ COOH ethoxy CO Phenyl OCH₂CH₂CH₃ COOH ethoxy COPhenyl OCH₂CH₂CH₂CH₃ COOH ethoxy CO Phenyl OCH₂CH₂CH₂CH₂CH₃ COOH ethoxyCO Phenyl C5-C8 alkoxy COOH ethoxy CO Phenyl Halo substituted alkoxyCOOH ethoxy CO Phenyl CH₃ COOH ethoxy CO Phenyl CH₂CH₃ COOH ethoxy COPhenyl CH₂CH₂CH₃ COOH ethoxy CO Phenyl CH₂CH₂CH₂CH₃ COOH ethoxy COPhenyl C5-C8 alkyl COOH ethoxy CO Phenyl F COOH ethoxy CO Phenyl F,FCOOH ethoxy CO Phenyl F,Cl COOH ethoxy CO Phenyl Cl COOH ethoxy COPhenyl Cl,Cl COOH ethoxy CO Phenyl -(1 to 4 linearly linked COOH ethoxyatom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearly linkedCOOH ethoxy atom linker)-optionally subst. heteroaryl CO pyridinyl COOHethoxy CO Pyridinyl CF₃ COOH ethoxy CO Pyridinyl CH₂CF₃ COOH ethoxy COPyridinyl Halo substituted alkyl COOH ethoxy CO Pyridinyl OCH₃ COOHethoxy CO Pyridinyl OCH₂CH₃ COOH ethoxy CO Pyridinyl OCH₂CH₂CH₃ COOHethoxy CO Pyridinyl OCH₂CH₂CH₂CH₃ COOH ethoxy CO PyridinylOCH₂CH₂CH₂CH₂CH₃ COOH ethoxy CO Pyridinyl C5-C8 alkoxy COOH ethoxy COPyridinyl Halo substituted alkoxy COOH ethoxy CO Pyridinyl CH₃ COOHethoxy CO Pyridinyl CH₂CH₃ COOH ethoxy CO Pyridinyl CH₂CH₂CH₃ COOHethoxy CO Pyridinyl CH₂CH₂CH₂CH₃ COOH ethoxy CO Pyridinyl C5-C8 alkylCOOH ethoxy CO Pyridinyl F COOH ethoxy CO Pyridinyl F,F COOH ethoxy COPyridinyl F,Cl COOH ethoxy CO Pyridinyl Cl COOH ethoxy CO PyridinylCl,Cl COOH ethoxy CO Pyridinyl -(1 to 4 linearly linked COOH ethoxy atomlinker)-optionally subst. aryl CO Pyridinyl -(1 to 4 linearly linkedCOOH ethoxy atom linker)-optionally subst. heteroaryl SO₂ phenyl COOHpropoxy SO₂ phenyl CF₃ COOH propoxy SO₂ phenyl CH₂CF₃ COOH propoxy SO₂phenyl Halo substituted alkyl COOH propoxy SO₂ phenyl OCH₃ COOH propoxySO₂ phenyl OCH₂CH₃ COOH propoxy SO₂ phenyl OCH₂CH₂CH₃ COOH propoxy SO₂phenyl OCH₂CH₂CH₂CH₃ COOH propoxy SO₂ phenyl OCH₂CH₂CH₂CH₂CH₃ COOHpropoxy SO₂ phenyl C5-C8 alkoxy COOH propoxy SO₂ phenyl Halo substitutedalkoxy COOH propoxy SO₂ phenyl CH₃ COOH propoxy SO₂ phenyl CH₂CH₃ COOHpropoxy SO₂ phenyl CH₂CH₂CH₃ COOH propoxy SO₂ phenyl CH₂CH₂CH₂CH₃ COOHpropoxy SO₂ phenyl C5-C8 alkyl COOH propoxy SO₂ phenyl F COOH propoxySO₂ phenyl F,F COOH propoxy SO₂ phenyl F,Cl COOH propoxy SO₂ phenyl ClCOOH propoxy SO₂ phenyl Cl,Cl COOH propoxy SO₂ phenyl -(1 to 4 linearlylinked COOH propoxy atom linker)-optionally subst. aryl SO₂ phenyl -(1to 4 linearly linked COOH propoxy atom linker)-optionally subst.heteroaryl SO₂ pyridinyl COOH propoxy SO₂ Pyridinyl CF₃ COOH propoxy SO₂Pyridinyl CH₂CF₃ COOH propoxy SO₂ Pyridinyl Halo substituted alkyl COOHpropoxy SO₂ Pyridinyl OCH₃ COOH propoxy SO₂ Pyridinyl OCH₂CH₃ COOHpropoxy SO₂ Pyridinyl OCH₂CH₂CH₃ COOH propoxy SO₂ PyridinylOCH₂CH₂CH₂CH₃ COOH propoxy SO₂ Pyridinyl OCH₂CH₂CH₂CH₂CH₃ COOH propoxySO₂ Pyridinyl C5-C8 alkoxy COOH propoxy SO₂ Pyridinyl Halo substitutedalkoxy COOH propoxy SO₂ Pyridinyl CH₃ COOH propoxy SO₂ Pyridinyl CH₂CH₃COOH propoxy SO₂ Pyridinyl CH₂CH₂CH₃ COOH propoxy SO₂ PyridinylCH₂CH₂CH₂CH₃ COOH propoxy SO₂ Pyridinyl C5-C8 alkyl COOH propoxy SO₂Pyridinyl F COOH propoxy SO₂ Pyridinyl F,F COOH propoxy SO₂ PyridinylF,Cl COOH propoxy SO₂ Pyridinyl Cl COOH propoxy SO₂ Pyridinyl Cl,Cl COOHpropoxy SO₂ Pyridinyl -(1 to 4 linearly linked COOH propoxy atomlinker)-optionally subst. aryl SO₂ Pyridinyl -(1 to 4 linearly linkedCOOH propoxy atom linker)-optionally subst. heteroaryl CO Phenyl COOHpropoxy CO Phenyl CF₃ COOH propoxy CO Phenyl CH₂CF₃ COOH propoxy COPhenyl Halo substituted alkyl COOH propoxy CO Phenyl OCH₃ COOH propoxyCO Phenyl OCH₂CH₃ COOH propoxy CO Phenyl OCH₂CH₂CH₃ COOH propoxy COPhenyl OCH₂CH₂CH₂CH₃ COOH propoxy CO Phenyl OCH₂CH₂CH₂CH₂CH₃ COOHpropoxy CO Phenyl C5-C8 alkoxy COOH propoxy CO Phenyl Halo substitutedalkoxy COOH propoxy CO Phenyl CH₃ COOH propoxy CO Phenyl CH₂CH₃ COOHpropoxy CO Phenyl CH₂CH₂CH₃ COOH propoxy CO Phenyl CH₂CH₂CH₂CH₃ COOHpropoxy CO Phenyl C5-C8 alkyl COOH propoxy CO Phenyl F COOH propoxy COPhenyl F,F COOH propoxy CO Phenyl F,Cl COOH propoxy CO Phenyl Cl COOHpropoxy CO Phenyl Cl,Cl COOH propoxy CO Phenyl -(1 to 4 linearly linkedCOOH propoxy atom linker)-optionally subst. aryl CO Phenyl -(1 to 4linearly linked COOH propoxy atom linker)-optionally subst. heteroarylCO pyridinyl COOH propoxy CO Pyridinyl CF₃ COOH propoxy CO PyridinylCH₂CF₃ COOH propoxy CO Pyridinyl Halo substituted alkyl COOH propoxy COPyridinyl OCH₃ COOH propoxy CO Pyridinyl OCH₂CH₃ COOH propoxy COPyridinyl OCH₂CH₂CH₃ COOH propoxy CO Pyridinyl OCH₂CH₂CH₂CH₃ COOHpropoxy CO Pyridinyl OCH₂CH₂CH₂CH₂CH₃ COOH propoxy CO Pyridinyl C5-C8alkoxy COOH propoxy CO Pyridinyl Halo substituted alkoxy COOH propoxy COPyridinyl CH₃ COOH propoxy CO Pyridinyl CH₂CH₃ COOH propoxy CO PyridinylCH₂CH₂CH₃ COOH propoxy CO Pyridinyl CH₂CH₂CH₂CH₃ COOH propoxy COPyridinyl C5-C8 alkyl COOH propoxy CO Pyridinyl F COOH propoxy COPyridinyl F,F COOH propoxy CO Pyridinyl F,Cl COOH propoxy CO PyridinylCl COOH propoxy CO Pyridinyl Cl,Cl COOH propoxy CO Pyridinyl -(1 to 4linearly linked COOH propoxy atom linker)-optionally subst. aryl COPyridinyl -(1 to 4 linearly linked COOH propoxy atom linker)-optionallysubst. heteroaryl SO₂ phenyl COOH —SCH₃ SO₂ phenyl CF₃ COOH —SCH₃ SO₂phenyl CH₂CF₃ COOH —SCH₃ SO₂ phenyl Halo substituted alkyl COOH —SCH₃SO₂ phenyl OCH₃ COOH —SCH₃ SO₂ phenyl OCH₂CH₃ COOH —SCH₃ SO₂ phenylOCH₂CH₂CH₃ COOH —SCH₃ SO₂ phenyl OCH₂CH₂CH₂CH₃ COOH —SCH₃ SO₂ phenylOCH₂CH₂CH₂CH₂CH₃ COOH —SCH₃ SO₂ phenyl C5-C8 alkoxy COOH —SCH₃ SO₂phenyl Halo substituted alkoxy COOH —SCH₃ SO₂ phenyl CH₃ COOH —SCH₃ SO₂phenyl CH₂CH₃ COOH —SCH₃ SO₂ phenyl CH₂CH₂CH₃ COOH —SCH₃ SO₂ phenylCH₂CH₂CH₂CH₃ COOH —SCH₃ SO₂ phenyl C5-C8 alkyl COOH —SCH₃ SO₂ phenyl FCOOH —SCH₃ SO₂ phenyl F,F COOH —SCH₃ SO₂ phenyl F,Cl COOH —SCH₃ SO₂phenyl Cl COOH —SCH₃ SO₂ phenyl Cl,Cl COOH —SCH₃ SO₂ phenyl -(1 to 4linearly linked COOH —SCH₃ atom linker)-optionally subst. aryl SO₂phenyl -(1 to 4 linearly linked COOH —SCH₃ atom linker)-optionallysubst. heteroaryl SO₂ pyridinyl COOH —SCH₃ SO₂ Pyridinyl CF₃ COOH —SCH₃SO₂ Pyridinyl CH₂CF₃ COOH —SCH₃ SO₂ Pyridinyl Halo substituted alkylCOOH —SCH₃ SO₂ Pyridinyl OCH₃ COOH —SCH₃ SO₂ Pyridinyl OCH₂CH₃ COOH—SCH₃ SO₂ Pyridinyl OCH₂CH₂CH₃ COOH —SCH₃ SO₂ Pyridinyl OCH₂CH₂CH₂CH₃COOH —SCH₃ SO₂ Pyridinyl OCH₂CH₂CH₂CH₂CH₃ COOH —SCH₃ SO₂ Pyridinyl C5-C8alkoxy COOH —SCH₃ SO₂ Pyridinyl Halo substituted alkoxy COOH —SCH₃ SO₂Pyridinyl CH₃ COOH —SCH₃ SO₂ Pyridinyl CH₂CH₃ COOH —SCH₃ SO₂ PyridinylCH₂CH₂CH₃ COOH —SCH₃ SO₂ Pyridinyl CH₂CH₂CH₂CH₃ COOH —SCH₃ SO₂ PyridinylC5-C8 alkyl COOH —SCH₃ SO₂ Pyridinyl F COOH —SCH₃ SO₂ Pyridinyl F,F COOH—SCH₃ SO₂ Pyridinyl F,Cl COOH —SCH₃ SO₂ Pyridinyl Cl COOH —SCH₃ SO₂Pyridinyl Cl,Cl COOH —SCH₃ SO₂ Pyridinyl -(1 to 4 linearly linked COOH—SCH₃ atom linker)-optionally subst. aryl SO₂ Pyridinyl -(1 to 4linearly linked COOH —SCH₃ atom linker)-optionally subst. heteroaryl COPhenyl COOH —SCH₃ CO Phenyl CF₃ COOH —SCH₃ CO Phenyl CH₂CF₃ COOH —SCH₃CO Phenyl Halo substituted alkyl COOH —SCH₃ CO Phenyl OCH₃ COOH —SCH₃ COPhenyl OCH₂CH₃ COOH —SCH₃ CO Phenyl OCH₂CH₂CH₃ COOH —SCH₃ CO PhenylOCH₂CH₂CH₂CH₃ COOH —SCH₃ CO Phenyl OCH₂CH₂CH₂CH₂CH₃ COOH —SCH₃ CO PhenylC5-C8 alkoxy COOH —SCH₃ CO Phenyl Halo substituted alkoxy COOH —SCH₃ COPhenyl CH₃ COOH —SCH₃ CO Phenyl CH₂CH₃ COOH —SCH₃ CO Phenyl CH₂CH₂CH₃COOH —SCH₃ CO Phenyl CH₂CH₂CH₂CH₃ COOH —SCH₃ CO Phenyl C5-C8 alkyl COOH—SCH₃ CO Phenyl F COOH —SCH₃ CO Phenyl F,F COOH —SCH₃ CO Phenyl F,ClCOOH —SCH₃ CO Phenyl Cl COOH —SCH₃ CO Phenyl Cl,Cl COOH —SCH₃ CO Phenyl-(1 to 4 linearly linked COOH —SCH₃ atom linker)-optionally subst. arylCO Phenyl -(1 to 4 linearly linked COOH —SCH₃ atom linker)-optionallysubst. heteroaryl CO pyridinyl COOH —SCH₃ CO Pyridinyl CF₃ COOH —SCH₃ COPyridinyl CH₂CF₃ COOH —SCH₃ CO Pyridinyl Halo substituted alkyl COOH—SCH₃ CO Pyridinyl OCH₃ COOH —SCH₃ CO Pyridinyl OCH₂CH₃ COOH —SCH₃ COPyridinyl OCH₂CH₂CH₃ COOH —SCH₃ CO Pyridinyl OCH₂CH₂CH₂CH₃ COOH —SCH₃ COPyridinyl OCH₂CH₂CH₂CH₂CH₃ COOH —SCH₃ CO Pyridinyl C5-C8 alkoxy COOH—SCH₃ CO Pyridinyl Halo substituted alkoxy COOH —SCH₃ CO Pyridinyl CH₃COOH —SCH₃ CO Pyridinyl CH₂CH₃ COOH —SCH₃ CO Pyridinyl CH₂CH₂CH₃ COOH—SCH₃ CO Pyridinyl CH₂CH₂CH₂CH₃ COOH —SCH₃ CO Pyridinyl C5-C8 alkyl COOH—SCH₃ CO Pyridinyl F COOH —SCH₃ CO Pyridinyl F,F COOH —SCH₃ CO PyridinylF,Cl COOH —SCH₃ CO Pyridinyl Cl COOH —SCH₃ CO Pyridinyl Cl,Cl COOH —SCH₃CO Pyridinyl -(1 to 4 linearly linked COOH —SCH₃ atom linker)-optionallysubst. aryl CO Pyridinyl -(1 to 4 linearly linked COOH —SCH₃ atomlinker)-optionally subst. heteroaryl SO₂ phenyl COOH —SCH₂CH₃ SO₂ phenylCF₃ COOH —SCH₂CH₃ SO₂ phenyl CH₂CF₃ COOH —SCH₂CH₃ SO₂ phenyl Halosubstituted alkyl COOH —SCH₂CH₃ SO₂ phenyl OCH₃ COOH —SCH₂CH₃ SO₂ phenylOCH₂CH₃ COOH —SCH₂CH₃ SO₂ phenyl OCH₂CH₂CH₃ COOH —SCH₂CH₃ SO₂ phenylOCH₂CH₂CH₂CH₃ COOH —SCH₂CH₃ SO₂ phenyl OCH₂CH₂CH₂CH₂CH₃ COOH —SCH₂CH₃SO₂ phenyl C5-C8 alkoxy COOH —SCH₂CH₃ SO₂ phenyl Halo substituted alkoxyCOOH —SCH₂CH₃ SO₂ phenyl CH₃ COOH —SCH₂CH₃ SO₂ phenyl CH₂CH₃ COOH—SCH₂CH₃ SO₂ phenyl CH₂CH₂CH₃ COOH —SCH₂CH₃ SO₂ phenyl CH₂CH₂CH₂CH₃ COOH—SCH₂CH₃ SO₂ phenyl C5-C8 alkyl COOH —SCH₂CH₃ SO₂ phenyl F COOH —SCH₂CH₃SO₂ phenyl F,F COOH —SCH₂CH₃ SO₂ phenyl F,Cl COOH —SCH₂CH₃ SO₂ phenyl ClCOOH —SCH₂CH₃ SO₂ phenyl Cl,Cl COOH —SCH₂CH₃ SO₂ phenyl -(1 to 4linearly linked COOH —SCH₂CH₃ atom linker)-optionally subst. aryl SO₂phenyl -(1 to 4 linearly linked COOH —SCH₂CH₃ atom linker)-optionallysubst. heteroaryl SO₂ pyridinyl COOH —SCH₂CH₃ SO₂ Pyridinyl CF₃ COOH—SCH₂CH₃ SO₂ Pyridinyl CH₂CF₃ COOH —SCH₂CH₃ SO₂ Pyridinyl Halosubstituted alkyl COOH —SCH₂CH₃ SO₂ Pyridinyl OCH₃ COOH —SCH₂CH₃ SO₂Pyridinyl OCH₂CH₃ COOH —SCH₂CH₃ SO₂ Pyridinyl OCH₂CH₂CH₃ COOH —SCH₂CH₃SO₂ Pyridinyl OCH₂CH₂CH₂CH₃ COOH —SCH₂CH₃ SO₂ Pyridinyl OCH₂CH₂CH₂CH₂CH₃COOH —SCH₂CH₃ SO₂ Pyridinyl C5-C8 alkoxy COOH —SCH₂CH₃ SO₂ PyridinylHalo substituted alkoxy COOH —SCH₂CH₃ SO₂ Pyridinyl CH₃ COOH —SCH₂CH₃SO₂ Pyridinyl CH₂CH₃ COOH —SCH₂CH₃ SO₂ Pyridinyl CH₂CH₂CH₃ COOH —SCH₂CH₃SO₂ Pyridinyl CH₂CH₂CH₂CH₃ COOH —SCH₂CH₃ SO₂ Pyridinyl C5-C8 alkyl COOH—SCH₂CH₃ SO₂ Pyridinyl F COOH —SCH₂CH₃ SO₂ Pyridinyl F,F COOH —SCH₂CH₃SO₂ Pyridinyl F,Cl COOH —SCH₂CH₃ SO₂ Pyridinyl Cl COOH —SCH₂CH₃ SO₂Pyridinyl Cl,Cl COOH —SCH₂CH₃ SO₂ Pyridinyl -(1 to 4 linearly linkedCOOH —SCH₂CH₃ atom linker)-optionally subst. aryl SO₂ Pyridinyl -(1 to 4linearly linked COOH —SCH₂CH₃ atom linker)-optionally subst. heteroarylCO Phenyl COOH —SCH₂CH₃ CO Phenyl CF₃ COOH —SCH₂CH₃ CO Phenyl CH₂CF₃COOH —SCH₂CH₃ CO Phenyl Halo substituted alkyl COOH —SCH₂CH₃ CO PhenylOCH₃ COOH —SCH₂CH₃ CO Phenyl OCH₂CH₃ COOH —SCH₂CH₃ CO Phenyl OCH₂CH₂CH₃COOH —SCH₂CH₃ CO Phenyl OCH₂CH₂CH₂CH₃ COOH —SCH₂CH₃ CO PhenylOCH₂CH₂CH₂CH₂CH₃ COOH —SCH₂CH₃ CO Phenyl C5-C8 alkoxy COOH —SCH₂CH₃ COPhenyl Halo substituted alkoxy COOH —SCH₂CH₃ CO Phenyl CH₃ COOH —SCH₂CH₃CO Phenyl CH₂CH₃ COOH —SCH₂CH₃ CO Phenyl CH₂CH₂CH₃ COOH —SCH₂CH₃ COPhenyl CH₂CH₂CH₂CH₃ COOH —SCH₂CH₃ CO Phenyl C5-C8 alkyl COOH —SCH₂CH₃ COPhenyl F COOH —SCH₂CH₃ CO Phenyl F,F COOH —SCH₂CH₃ CO Phenyl F,Cl COOH—SCH₂CH₃ CO Phenyl Cl COOH —SCH₂CH₃ CO Phenyl Cl,Cl COOH —SCH₂CH₃ COPhenyl -(1 to 4 linearly linked COOH —SCH₂CH₃ atom linker)-optionallysubst. aryl CO Phenyl -(1 to 4 linearly linked COOH —SCH₂CH₃ atomlinker)-optionally subst. heteroaryl CO pyridinyl COOH —SCH₂CH₃ COPyridinyl CF₃ COOH —SCH₂CH₃ CO Pyridinyl CH₂CF₃ COOH —SCH₂CH₃ COPyridinyl Halo substituted alkyl COOH —SCH₂CH₃ CO Pyridinyl OCH₃ COOH—SCH₂CH₃ CO Pyridinyl OCH₂CH₃ COOH —SCH₂CH₃ CO Pyridinyl OCH₂CH₂CH₃ COOH—SCH₂CH₃ CO Pyridinyl OCH₂CH₂CH₂CH₃ COOH —SCH₂CH₃ CO PyridinylOCH₂CH₂CH₂CH₂CH₃ COOH —SCH₂CH₃ CO Pyridinyl C5-C8 alkoxy COOH —SCH₂CH₃CO Pyridinyl Halo substituted alkoxy COOH —SCH₂CH₃ CO Pyridinyl CH₃ COOH—SCH₂CH₃ CO Pyridinyl CH₂CH₃ COOH —SCH₂CH₃ CO Pyridinyl CH₂CH₂CH₃ COOH—SCH₂CH₃ CO Pyridinyl CH₂CH₂CH₂CH₃ COOH —SCH₂CH₃ CO Pyridinyl C5-C8alkyl COOH —SCH₂CH₃ CO Pyridinyl F COOH —SCH₂CH₃ CO Pyridinyl F,F COOH—SCH₂CH₃ CO Pyridinyl F,Cl COOH —SCH₂CH₃ CO Pyridinyl Cl COOH —SCH₂CH₃CO Pyridinyl Cl,Cl COOH —SCH₂CH₃ CO Pyridinyl -(1 to 4 linearly linkedCOOH —SCH₂CH₃ atom linker)-optionally subst. aryl CO Pyridinyl -(1 to 4linearly linked COOH —SCH₂CH₃ atom linker)-optionally subst. heteroarylSO₂ phenyl tetrazole methoxy SO₂ phenyl CF₃ Tetrazole methoxy SO₂ phenylCH₂CF₃ Tetrazole methoxy SO₂ phenyl Halo substituted alkyl Tetrazolemethoxy SO₂ phenyl OCH₃ Tetrazole methoxy SO₂ phenyl OCH₂CH₃ tetrazolemethoxy SO₂ phenyl OCH₂CH₂CH₃ tetrazole methoxy SO₂ phenyl OCH₂CH₂CH₂CH₃Tetrazole methoxy SO₂ phenyl OCH₂CH₂CH₂CH₂CH₃ Tetrazole methoxy SO₂phenyl C5-C8 alkoxy Tetrazole methoxy SO₂ phenyl Halo substituted alkoxyTetrazole methoxy SO₂ phenyl CH₃ tetrazole methoxy SO₂ phenyl CH₂CH₃tetrazole methoxy SO₂ phenyl CH₂CH₂CH₃ Tetrazole methoxy SO₂ phenylCH₂CH₂CH₂CH₃ Tetrazole methoxy SO₂ phenyl C5-C8 alkyl Tetrazole methoxySO₂ phenyl F Tetrazole methoxy SO₂ phenyl F,F tetrazole methoxy SO₂phenyl F,Cl tetrazole methoxy SO₂ phenyl Cl Tetrazole methoxy SO₂ phenylCl,Cl Tetrazole methoxy SO₂ phenyl -(1 to 4 linearly linked Tetrazolemethoxy atom linker)-optionally subst. aryl SO₂ phenyl -(1 to 4 linearlylinked Tetrazole methoxy atom linker)-optionally subst. heteroaryl SO₂pyridinyl tetrazole methoxy SO₂ Pyridinyl CF₃ tetrazole methoxy SO₂Pyridinyl CH₂CF₃ Tetrazole methoxy SO₂ Pyridinyl Halo substituted alkylTetrazole methoxy SO₂ Pyridinyl OCH₃ Tetrazole methoxy SO₂ PyridinylOCH₂CH₃ Tetrazole methoxy SO₂ Pyridinyl OCH₂CH₂CH₃ tetrazole methoxy SO₂Pyridinyl OCH₂CH₂CH₂CH₃ tetrazole methoxy SO₂ Pyridinyl OCH₂CH₂CH₂CH₂CH₃Tetrazole methoxy SO₂ Pyridinyl C5-C8 alkoxy Tetrazole methoxy SO₂Pyridinyl Halo substituted alkoxy Tetrazole methoxy SO₂ Pyridinyl CH₃Tetrazole methoxy SO₂ Pyridinyl CH₂CH₃ tetrazole methoxy SO₂ PyridinylCH₂CH₂CH₃ tetrazole methoxy SO₂ Pyridinyl CH₂CH₂CH₂CH₃ Tetrazole methoxySO₂ Pyridinyl C5-C8 alkyl Tetrazole methoxy SO₂ Pyridinyl F Tetrazolemethoxy SO₂ Pyridinyl F,F Tetrazole methoxy SO₂ Pyridinyl F,Cl tetrazolemethoxy SO₂ Pyridinyl Cl tetrazole methoxy SO₂ Pyridinyl Cl,Cl Tetrazolemethoxy SO₂ Pyridinyl -(1 to 4 linearly linked Tetrazole methoxy atomlinker)-optionally subst. aryl SO₂ Pyridinyl -(1 to 4 linearly linkedTetrazole methoxy atom linker)-optionally subst. heteroaryl CO PhenylTetrazole methoxy CO Phenyl CF₃ tetrazole methoxy CO Phenyl CH₂CF₃tetrazole methoxy CO Phenyl Halo substituted alkyl Tetrazole methoxy COPhenyl OCH₃ Tetrazole methoxy CO Phenyl OCH₂CH₃ Tetrazole methoxy COPhenyl OCH₂CH₂CH₃ Tetrazole methoxy CO Phenyl OCH₂CH₂CH₂CH₃ tetrazolemethoxy CO Phenyl OCH₂CH₂CH₂CH₂CH₃ tetrazole methoxy CO Phenyl C5-C8alkoxy Tetrazole methoxy CO Phenyl Halo substituted alkoxy Tetrazolemethoxy CO Phenyl CH₃ Tetrazole methoxy CO Phenyl CH₂CH₃ Tetrazolemethoxy CO Phenyl CH₂CH₂CH₃ tetrazole methoxy CO Phenyl CH₂CH₂CH₂CH₃tetrazole methoxy CO Phenyl C5-C8 alkyl Tetrazole methoxy CO Phenyl FTetrazole methoxy CO Phenyl F,F Tetrazole methoxy CO Phenyl F,ClTetrazole methoxy CO Phenyl Cl tetrazole methoxy CO Phenyl Cl,Cltetrazole methoxy CO Phenyl -(1 to 4 linearly linked Tetrazole methoxyatom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearly linkedTetrazole methoxy atom linker)-optionally subst. heteroaryl CO pyridinylTetrazole methoxy CO Pyridinyl CF₃ Tetrazole methoxy CO Pyridinyl CH₂CF₃tetrazole methoxy CO Pyridinyl Halo substituted alkyl tetrazole methoxyCO Pyridinyl OCH₃ Tetrazole methoxy CO Pyridinyl OCH₂CH₃ Tetrazolemethoxy CO Pyridinyl OCH₂CH₂CH₃ Tetrazole methoxy CO PyridinylOCH₂CH₂CH₂CH₃ Tetrazole methoxy CO Pyridinyl OCH₂CH₂CH₂CH₂CH₃ tetrazolemethoxy CO Pyridinyl C5-C8 alkoxy tetrazole methoxy CO Pyridinyl Halosubstituted alkoxy Tetrazole methoxy CO Pyridinyl CH₃ Tetrazole methoxyCO Pyridinyl CH₂CH₃ Tetrazole methoxy CO Pyridinyl CH₂CH₂CH₃ Tetrazolemethoxy CO Pyridinyl CH₂CH₂CH₂CH₃ tetrazole methoxy CO Pyridinyl C5-C8alkyl tetrazole methoxy CO Pyridinyl F Tetrazole methoxy CO PyridinylF,F Tetrazole methoxy CO Pyridinyl F,Cl Tetrazole methoxy CO PyridinylCl Tetrazole methoxy CO Pyridinyl Cl,Cl tetrazole methoxy CO Pyridinyl-(1 to 4 linearly linked tetrazole methoxy atom linker)-optionallysubst. aryl CO Pyridinyl -(1 to 4 linearly linked Tetrazole methoxy atomlinker)-optionally subst. heteroaryl SO₂ phenyl Tetrazole ethoxy SO₂phenyl CF₃ Tetrazole ethoxy SO₂ phenyl CH₂CF₃ Tetrazole ethoxy SO₂phenyl Halo substituted alkyl tetrazole ethoxy SO₂ phenyl OCH₃ tetrazoleethoxy SO₂ phenyl OCH₂CH₃ Tetrazole ethoxy SO₂ phenyl OCH₂CH₂CH₃Tetrazole ethoxy SO₂ phenyl OCH₂CH₂CH₂CH₃ Tetrazole ethoxy SO₂ phenylOCH₂CH₂CH₂CH₂CH₃ Tetrazole ethoxy SO₂ phenyl C5-C8 alkoxy tetrazoleethoxy SO₂ phenyl Halo substituted alkoxy tetrazole ethoxy SO₂ phenylCH₃ Tetrazole ethoxy SO₂ phenyl CH₂CH₃ Tetrazole ethoxy SO₂ phenylCH₂CH₂CH₃ Tetrazole ethoxy SO₂ phenyl CH₂CH₂CH₂CH₃ Tetrazole ethoxy SO₂phenyl C5-C8 alkyl tetrazole ethoxy SO₂ phenyl F tetrazole ethoxy SO₂phenyl F,F Tetrazole ethoxy SO₂ phenyl F,Cl Tetrazole ethoxy SO₂ phenylCl Tetrazole ethoxy SO₂ phenyl Cl,Cl Tetrazole ethoxy SO₂ phenyl -(1 to4 linearly linked tetrazole ethoxy atom linker)-optionally subst. arylSO₂ phenyl -(1 to 4 linearly linked tetrazole ethoxy atomlinker)-optionally subst. heteroaryl SO₂ pyridinyl Tetrazole ethoxy SO₂Pyridinyl CF₃ Tetrazole ethoxy SO₂ Pyridinyl CH₂CF₃ Tetrazole ethoxy SO₂Pyridinyl Halo substituted alkyl Tetrazole ethoxy SO₂ Pyridinyl OCH₃tetrazole ethoxy SO₂ Pyridinyl OCH₂CH₃ tetrazole ethoxy SO₂ PyridinylOCH₂CH₂CH₃ Tetrazole ethoxy SO₂ Pyridinyl OCH₂CH₂CH₂CH₃ Tetrazole ethoxySO₂ Pyridinyl OCH₂CH₂CH₂CH₂CH₃ Tetrazole ethoxy SO₂ Pyridinyl C5-C8alkoxy Tetrazole ethoxy SO₂ Pyridinyl Halo substituted alkoxy tetrazoleethoxy SO₂ Pyridinyl CH₃ tetrazole ethoxy SO₂ Pyridinyl CH₂CH₃ Tetrazoleethoxy SO₂ Pyridinyl CH₂CH₂CH₃ Tetrazole ethoxy SO₂ PyridinylCH₂CH₂CH₂CH₃ Tetrazole ethoxy SO₂ Pyridinyl C5-C8 alkyl Tetrazole ethoxySO₂ Pyridinyl F tetrazole ethoxy SO₂ Pyridinyl F,F tetrazole ethoxy SO₂Pyridinyl F,Cl Tetrazole ethoxy SO₂ Pyridinyl Cl Tetrazole ethoxy SO₂Pyridinyl Cl,Cl Tetrazole ethoxy SO₂ Pyridinyl -(1 to 4 linearly linkedTetrazole ethoxy atom linker)-optionally subst. aryl SO₂ Pyridinyl -(1to 4 linearly linked tetrazole ethoxy atom linker)-optionally subst.heteroaryl CO Phenyl tetrazole ethoxy CO Phenyl CF₃ Tetrazole ethoxy COPhenyl CH₂CF₃ Tetrazole ethoxy CO Phenyl Halo substituted alkylTetrazole ethoxy CO Phenyl OCH₃ Tetrazole ethoxy CO Phenyl OCH₂CH₃tetrazole ethoxy CO Phenyl OCH₂CH₂CH₃ tetrazole ethoxy CO PhenylOCH₂CH₂CH₂CH₃ Tetrazole ethoxy CO Phenyl OCH₂CH₂CH₂CH₂CH₃ Tetrazoleethoxy CO Phenyl C5-C8 alkoxy Tetrazole ethoxy CO Phenyl Halosubstituted alkoxy Tetrazole ethoxy CO Phenyl CH₃ tetrazole ethoxy COPhenyl CH₂CH₃ tetrazole ethoxy CO Phenyl CH₂CH₂CH₃ Tetrazole ethoxy COPhenyl CH₂CH₂CH₂CH₃ Tetrazole ethoxy CO Phenyl C5-C8 alkyl Tetrazoleethoxy CO Phenyl F Tetrazole ethoxy CO Phenyl F,F tetrazole ethoxy COPhenyl F,Cl tetrazole ethoxy CO Phenyl Cl Tetrazole ethoxy CO PhenylCl,Cl Tetrazole ethoxy CO Phenyl -(1 to 4 linearly linked Tetrazoleethoxy atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearlylinked Tetrazole ethoxy atom linker)-optionally subst. heteroaryl COpyridinyl tetrazole ethoxy CO Pyridinyl CF₃ tetrazole ethoxy COPyridinyl CH₂CF₃ Tetrazole ethoxy CO Pyridinyl Halo substituted alkylTetrazole ethoxy CO Pyridinyl OCH₃ Tetrazole ethoxy CO Pyridinyl OCH₂CH₃Tetrazole ethoxy CO Pyridinyl OCH₂CH₂CH₃ tetrazole ethoxy CO PyridinylOCH₂CH₂CH₂CH₃ tetrazole ethoxy CO Pyridinyl OCH₂CH₂CH₂CH₂CH₃ Tetrazoleethoxy CO Pyridinyl C5-C8 alkoxy Tetrazole ethoxy CO Pyridinyl Halosubstituted alkoxy Tetrazole ethoxy CO Pyridinyl CH₃ Tetrazole ethoxy COPyridinyl CH₂CH₃ tetrazole ethoxy CO Pyridinyl CH₂CH₂CH₃ tetrazoleethoxy CO Pyridinyl CH₂CH₂CH₂CH₃ Tetrazole ethoxy CO Pyridinyl C5-C8alkyl Tetrazole ethoxy CO Pyridinyl F Tetrazole ethoxy CO Pyridinyl F,FTetrazole ethoxy CO Pyridinyl F,Cl tetrazole ethoxy CO Pyridinyl Cltetrazole ethoxy CO Pyridinyl Cl,Cl Tetrazole ethoxy CO Pyridinyl -(1 to4 linearly linked Tetrazole ethoxy atom linker)-optionally subst. arylCO Pyridinyl -(1 to 4 linearly linked Tetrazole ethoxy atomlinker)-optionally subst. heteroaryl SO₂ phenyl tetrazole propoxy SO₂phenyl CF₃ Tetrazole propoxy SO₂ phenyl CH₂CF₃ Tetrazole propoxy SO₂phenyl Halo substituted alkyl Tetrazole propoxy SO₂ phenyl OCH₃Tetrazole propoxy SO₂ phenyl OCH₂CH₃ tetrazole propoxy SO₂ phenylOCH₂CH₂CH₃ tetrazole propoxy SO₂ phenyl OCH₂CH₂CH₂CH₃ Tetrazole propoxySO₂ phenyl OCH₂CH₂CH₂CH₂CH₃ Tetrazole propoxy SO₂ phenyl C5-C8 alkoxyTetrazole propoxy SO₂ phenyl Halo substituted alkoxy Tetrazole propoxySO₂ phenyl CH₃ tetrazole propoxy SO₂ phenyl CH₂CH₃ tetrazole propoxy SO₂phenyl CH₂CH₂CH₃ Tetrazole propoxy SO₂ phenyl CH₂CH₂CH₂CH₃ Tetrazolepropoxy SO₂ phenyl C5-C8 alkyl Tetrazole propoxy SO₂ phenyl F Tetrazolepropoxy SO₂ phenyl F,F tetrazole propoxy SO₂ phenyl F,Cl tetrazolepropoxy SO₂ phenyl Cl Tetrazole propoxy SO₂ phenyl Cl,Cl Tetrazolepropoxy SO₂ phenyl -(1 to 4 linearly linked Tetrazole propoxy atomlinker)-optionally subst. aryl SO₂ phenyl -(1 to 4 linearly linkedTetrazole propoxy atom linker)-optionally subst. heteroaryl SO₂pyridinyl tetrazole propoxy SO₂ Pyridinyl CF₃ tetrazole propoxy SO₂Pyridinyl CH₂CF₃ Tetrazole propoxy SO₂ Pyridinyl Halo substituted alkylTetrazole propoxy SO₂ Pyridinyl OCH₃ Tetrazole propoxy SO₂ PyridinylOCH₂CH₃ Tetrazole propoxy SO₂ Pyridinyl OCH₂CH₂CH₃ tetrazole propoxy SO₂Pyridinyl OCH₂CH₂CH₂CH₃ tetrazole propoxy SO₂ Pyridinyl OCH₂CH₂CH₂CH₂CH₃Tetrazole propoxy SO₂ Pyridinyl C5-C8 alkoxy Tetrazole propoxy SO₂Pyridinyl Halo substituted alkoxy Tetrazole propoxy SO₂ Pyridinyl CH₃Tetrazole propoxy SO₂ Pyridinyl CH₂CH₃ tetrazole propoxy SO₂ PyridinylCH₂CH₂CH₃ tetrazole propoxy SO₂ Pyridinyl CH₂CH₂CH₂CH₃ Tetrazole propoxySO₂ Pyridinyl C5-C8 alkyl Tetrazole propoxy SO₂ Pyridinyl F Tetrazolepropoxy SO₂ Pyridinyl F,F Tetrazole propoxy SO₂ Pyridinyl F,Cl tetrazolepropoxy SO₂ Pyridinyl Cl tetrazole propoxy SO₂ Pyridinyl Cl,Cl Tetrazolepropoxy SO₂ Pyridinyl -(1 to 4 linearly linked Tetrazole propoxy atomlinker)-optionally subst. aryl SO₂ Pyridinyl -(1 to 4 linearly linkedTetrazole propoxy atom linker)-optionally subst. heteroaryl CO PhenylTetrazole propoxy CO Phenyl CF₃ tetrazole propoxy CO Phenyl CH₂CF₃tetrazole propoxy CO Phenyl Halo substituted alkyl Tetrazole propoxy COPhenyl OCH₃ Tetrazole propoxy CO Phenyl OCH₂CH₃ Tetrazole propoxy COPhenyl OCH₂CH₂CH₃ Tetrazole propoxy CO Phenyl OCH₂CH₂CH₂CH₃ tetrazolepropoxy CO Phenyl OCH₂CH₂CH₂CH₂CH₃ tetrazole propoxy CO Phenyl C5-C8alkoxy Tetrazole propoxy CO Phenyl Halo substituted alkoxy Tetrazolepropoxy CO Phenyl CH₃ Tetrazole propoxy CO Phenyl CH₂CH₃ Tetrazolepropoxy CO Phenyl CH₂CH₂CH₃ tetrazole propoxy CO Phenyl CH₂CH₂CH₂CH₃tetrazole propoxy CO Phenyl C5-C8 alkyl Tetrazole propoxy CO Phenyl FTetrazole propoxy CO Phenyl F,F Tetrazole propoxy CO Phenyl F,ClTetrazole propoxy CO Phenyl Cl tetrazole propoxy CO Phenyl Cl,Cltetrazole propoxy CO Phenyl -(1 to 4 linearly linked Tetrazole propoxyatom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearly linkedTetrazole propoxy atom linker)-optionally subst. heteroaryl CO pyridinylTetrazole propoxy CO Pyridinyl CF₃ Tetrazole propoxy CO Pyridinyl CH₂CF₃tetrazole propoxy CO Pyridinyl Halo substituted alkyl tetrazole propoxyCO Pyridinyl OCH₃ Tetrazole propoxy CO Pyridinyl OCH₂CH₃ Tetrazolepropoxy CO Pyridinyl OCH₂CH₂CH₃ Tetrazole propoxy CO PyridinylOCH₂CH₂CH₂CH₃ Tetrazole propoxy CO Pyridinyl OCH₂CH₂CH₂CH₂CH₃ tetrazolepropoxy CO Pyridinyl C5-C8 alkoxy tetrazole propoxy CO Pyridinyl Halosubstituted alkoxy Tetrazole propoxy CO Pyridinyl CH₃ Tetrazole propoxyCO Pyridinyl CH₂CH₃ Tetrazole propoxy CO Pyridinyl CH₂CH₂CH₃ Tetrazolepropoxy CO Pyridinyl CH₂CH₂CH₂CH₃ tetrazole propoxy CO Pyridinyl C5-C8alkyl tetrazole propoxy CO Pyridinyl F Tetrazole propoxy CO PyridinylF,F Tetrazole propoxy CO Pyridinyl F,Cl Tetrazole propoxy CO PyridinylCl Tetrazole propoxy CO Pyridinyl Cl,Cl tetrazole propoxy CO Pyridinyl-(1 to 4 linearly linked tetrazole propoxy atom linker)-optionallysubst. aryl CO Pyridinyl -(1 to 4 linearly linked Tetrazole propoxy atomlinker)-optionally subst. heteroaryl SO₂ phenyl Tetrazole —SCH₃ SO₂phenyl CF₃ Tetrazole —SCH₃ SO₂ phenyl CH₂CF₃ Tetrazole —SCH₃ SO₂ phenylHalo substituted alkyl tetrazole —SCH₃ SO₂ phenyl OCH₃ tetrazole —SCH₃SO₂ phenyl OCH₂CH₃ Tetrazole —SCH₃ SO₂ phenyl OCH₂CH₂CH₃ Tetrazole —SCH₃SO₂ phenyl OCH₂CH₂CH₂CH₃ Tetrazole —SCH₃ SO₂ phenyl OCH₂CH₂CH₂CH₂CH₃Tetrazole —SCH₃ SO₂ phenyl C5-C8 alkoxy tetrazole —SCH₃ SO₂ phenyl Halosubstituted alkoxy tetrazole —SCH₃ SO₂ phenyl CH₃ Tetrazole —SCH₃ SO₂phenyl CH₂CH₃ Tetrazole —SCH₃ SO₂ phenyl CH₂CH₂CH₃ Tetrazole —SCH₃ SO₂phenyl CH₂CH₂CH₂CH₃ Tetrazole —SCH₃ SO₂ phenyl C5-C8 alkyl tetrazole—SCH₃ SO₂ phenyl F tetrazole —SCH₃ SO₂ phenyl F,F Tetrazole —SCH₃ SO₂phenyl F,Cl Tetrazole —SCH₃ SO₂ phenyl Cl Tetrazole —SCH₃ SO₂ phenylCl,Cl Tetrazole —SCH₃ SO₂ phenyl -(1 to 4 linearly linked tetrazole—SCH₃ atom linker)-optionally subst. aryl SO₂ phenyl -(1 to 4 linearlylinked tetrazole —SCH₃ atom linker)-optionally subst. heteroaryl SO₂pyridinyl Tetrazole —SCH₃ SO₂ Pyridinyl CF₃ Tetrazole —SCH₃ SO₂Pyridinyl CH₂CF₃ Tetrazole —SCH₃ SO₂ Pyridinyl Halo substituted alkylTetrazole —SCH₃ SO₂ Pyridinyl OCH₃ tetrazole —SCH₃ SO₂ Pyridinyl OCH₂CH₃tetrazole —SCH₃ SO₂ Pyridinyl OCH₂CH₂CH₃ Tetrazole —SCH₃ SO₂ PyridinylOCH₂CH₂CH₂CH₃ Tetrazole —SCH₃ SO₂ Pyridinyl OCH₂CH₂CH₂CH₂CH₃ Tetrazole—SCH₃ SO₂ Pyridinyl C5-C8 alkoxy Tetrazole —SCH₃ SO₂ Pyridinyl Halosubstituted alkoxy tetrazole —SCH₃ SO₂ Pyridinyl CH₃ tetrazole —SCH₃ SO₂Pyridinyl CH₂CH₃ Tetrazole —SCH₃ SO₂ Pyridinyl CH₂CH₂CH₃ Tetrazole —SCH₃SO₂ Pyridinyl CH₂CH₂CH₂CH₃ Tetrazole —SCH₃ SO₂ Pyridinyl C5-C8 alkylTetrazole —SCH₃ SO₂ Pyridinyl F tetrazole —SCH₃ SO₂ Pyridinyl F,Ftetrazole —SCH₃ SO₂ Pyridinyl F,Cl Tetrazole —SCH₃ SO₂ Pyridinyl ClTetrazole —SCH₃ SO₂ Pyridinyl Cl,Cl Tetrazole —SCH₃ SO₂ Pyridinyl -(1 to4 linearly linked Tetrazole —SCH₃ atom linker)-optionally subst. arylSO₂ Pyridinyl -(1 to 4 linearly linked tetrazole —SCH₃ atomlinker)-optionally subst. heteroaryl CO Phenyl tetrazole —SCH₃ CO PhenylCF₃ Tetrazole —SCH₃ CO Phenyl CH₂CF₃ Tetrazole —SCH₃ CO Phenyl Halosubstituted alkyl Tetrazole —SCH₃ CO Phenyl OCH₃ Tetrazole —SCH₃ COPhenyl OCH₂CH₃ tetrazole —SCH₃ CO Phenyl OCH₂CH₂CH₃ tetrazole —SCH₃ COPhenyl OCH₂CH₂CH₂CH₃ Tetrazole —SCH₃ CO Phenyl OCH₂CH₂CH₂CH₂CH₃Tetrazole —SCH₃ CO Phenyl C5-C8 alkoxy Tetrazole —SCH₃ CO Phenyl Halosubstituted alkoxy Tetrazole —SCH₃ CO Phenyl CH₃ tetrazole —SCH₃ COPhenyl CH₂CH₃ tetrazole —SCH₃ CO Phenyl CH₂CH₂CH₃ Tetrazole —SCH₃ COPhenyl CH₂CH₂CH₂CH₃ Tetrazole —SCH₃ CO Phenyl C5-C8 alkyl Tetrazole—SCH₃ CO Phenyl F Tetrazole —SCH₃ CO Phenyl F,F tetrazole —SCH₃ COPhenyl F,Cl tetrazole —SCH₃ CO Phenyl Cl Tetrazole —SCH₃ CO Phenyl Cl,ClTetrazole —SCH₃ CO Phenyl -(1 to 4 linearly linked Tetrazole —SCH₃ atomlinker)-optionally subst. aryl CO Phenyl -(1 to 4 linearly linkedTetrazole —SCH₃ atom linker)-optionally subst. heteroaryl CO pyridinyltetrazole —SCH₃ CO Pyridinyl CF₃ tetrazole —SCH₃ CO Pyridinyl CH₂CF₃Tetrazole —SCH₃ CO Pyridinyl Halo substituted alkyl Tetrazole —SCH₃ COPyridinyl OCH₃ Tetrazole —SCH₃ CO Pyridinyl OCH₂CH₃ Tetrazole —SCH₃ COPyridinyl OCH₂CH₂CH₃ tetrazole —SCH₃ CO Pyridinyl OCH₂CH₂CH₂CH₃tetrazole —SCH₃ CO Pyridinyl OCH₂CH₂CH₂CH₂CH₃ Tetrazole —SCH₃ COPyridinyl C5-C8 alkoxy Tetrazole —SCH₃ CO Pyridinyl Halo substitutedalkoxy Tetrazole —SCH₃ CO Pyridinyl CH₃ Tetrazole —SCH₃ CO PyridinylCH₂CH₃ tetrazole —SCH₃ CO Pyridinyl CH₂CH₂CH₃ tetrazole —SCH₃ COPyridinyl CH₂CH₂CH₂CH₃ Tetrazole —SCH₃ CO Pyridinyl C5-C8 alkylTetrazole —SCH₃ CO Pyridinyl F Tetrazole —SCH₃ CO Pyridinyl F,FTetrazole —SCH₃ CO Pyridinyl F,Cl tetrazole —SCH₃ CO Pyridinyl Cltetrazole —SCH₃ CO Pyridinyl Cl,Cl Tetrazole —SCH₃ CO Pyridinyl -(1 to 4linearly linked Tetrazole —SCH₃ atom linker)-optionally subst. aryl COPyridinyl -(1 to 4 linearly linked Tetrazole —SCH₃ atomlinker)-optionally subst. heteroaryl SO₂ phenyl Tetrazole —SCH₂CH₃ SO₂phenyl CF₃ tetrazole —SCH₂CH₃ SO₂ phenyl CH₂CF₃ tetrazole —SCH₂CH₃ SO₂phenyl Halo substituted alkyl Tetrazole —SCH₂CH₃ SO₂ phenyl OCH₃Tetrazole —SCH₂CH₃ SO₂ phenyl OCH₂CH₃ Tetrazole —SCH₂CH₃ SO₂ phenylOCH₂CH₂CH₃ Tetrazole —SCH₂CH₃ SO₂ phenyl OCH₂CH₂CH₂CH₃ tetrazole—SCH₂CH₃ SO₂ phenyl OCH₂CH₂CH₂CH₂CH₃ tetrazole —SCH₂CH₃ SO₂ phenyl C5-C8alkoxy Tetrazole —SCH₂CH₃ SO₂ phenyl Halo substituted alkoxy Tetrazole—SCH₂CH₃ SO₂ phenyl CH₃ Tetrazole —SCH₂CH₃ SO₂ phenyl CH₂CH₃ Tetrazole—SCH₂CH₃ SO₂ phenyl CH₂CH₂CH₃ tetrazole —SCH₂CH₃ SO₂ phenyl CH₂CH₂CH₂CH₃tetrazole —SCH₂CH₃ SO₂ phenyl C5-C8 alkyl Tetrazole —SCH₂CH₃ SO₂ phenylF Tetrazole —SCH₂CH₃ SO₂ phenyl F,F Tetrazole —SCH₂CH₃ SO₂ phenyl F,ClTetrazole —SCH₂CH₃ SO₂ phenyl Cl tetrazole —SCH₂CH₃ SO₂ phenyl Cl,Cltetrazole —SCH₂CH₃ SO₂ phenyl -(1 to 4 linearly linked Tetrazole—SCH₂CH₃ atom linker)-optionally subst. aryl SO₂ phenyl -(1 to 4linearly linked Tetrazole —SCH₂CH₃ atom linker)-optionally subst.heteroaryl SO₂ pyridinyl Tetrazole —SCH₂CH₃ SO₂ Pyridinyl CF₃ Tetrazole—SCH₂CH₃ SO₂ Pyridinyl CH₂CF₃ tetrazole —SCH₂CH₃ SO₂ Pyridinyl Halosubstituted alkyl tetrazole —SCH₂CH₃ SO₂ Pyridinyl OCH₃ Tetrazole—SCH₂CH₃ SO₂ Pyridinyl OCH₂CH₃ Tetrazole —SCH₂CH₃ SO₂ PyridinylOCH₂CH₂CH₃ Tetrazole —SCH₂CH₃ SO₂ Pyridinyl OCH₂CH₂CH₂CH₃ Tetrazole—SCH₂CH₃ SO₂ Pyridinyl OCH₂CH₂CH₂CH₂CH₃ tetrazole —SCH₂CH₃ SO₂ PyridinylC5-C8 alkoxy tetrazole —SCH₂CH₃ SO₂ Pyridinyl Halo substituted alkoxyTetrazole —SCH₂CH₃ SO₂ Pyridinyl CH₃ Tetrazole —SCH₂CH₃ SO₂ PyridinylCH₂CH₃ Tetrazole —SCH₂CH₃ SO₂ Pyridinyl CH₂CH₂CH₃ Tetrazole —SCH₂CH₃ SO₂Pyridinyl CH₂CH₂CH₂CH₃ tetrazole —SCH₂CH₃ SO₂ Pyridinyl C5-C8 alkyltetrazole —SCH₂CH₃ SO₂ Pyridinyl F Tetrazole —SCH₂CH₃ SO₂ Pyridinyl F,FTetrazole —SCH₂CH₃ SO₂ Pyridinyl F,Cl Tetrazole —SCH₂CH₃ SO₂ PyridinylCl Tetrazole —SCH₂CH₃ SO₂ Pyridinyl Cl,Cl tetrazole —SCH₂CH₃ SO₂Pyridinyl -(1 to 4 linearly linked tetrazole —SCH₂CH₃ atomlinker)-optionally subst. aryl SO₂ Pyridinyl -(1 to 4 linearly linkedTetrazole —SCH₂CH₃ atom linker)-optionally subst. heteroaryl CO PhenylTetrazole —SCH₂CH₃ CO Phenyl CF₃ Tetrazole —SCH₂CH₃ CO Phenyl CH₂CF₃Tetrazole —SCH₂CH₃ CO Phenyl Halo substituted alkyl tetrazole —SCH₂CH₃CO Phenyl OCH₃ tetrazole —SCH₂CH₃ CO Phenyl OCH₂CH₃ Tetrazole —SCH₂CH₃CO Phenyl OCH₂CH₂CH₃ Tetrazole —SCH₂CH₃ CO Phenyl OCH₂CH₂CH₂CH₃Tetrazole —SCH₂CH₃ CO Phenyl OCH₂CH₂CH₂CH₂CH₃ Tetrazole —SCH₂CH₃ COPhenyl C5-C8 alkoxy tetrazole —SCH₂CH₃ CO Phenyl Halo substituted alkoxytetrazole —SCH₂CH₃ CO Phenyl CH₃ Tetrazole —SCH₂CH₃ CO Phenyl CH₂CH₃Tetrazole —SCH₂CH₃ CO Phenyl CH₂CH₂CH₃ Tetrazole —SCH₂CH₃ CO PhenylCH₂CH₂CH₂CH₃ Tetrazole —SCH₂CH₃ CO Phenyl C5-C8 alkyl tetrazole —SCH₂CH₃CO Phenyl F tetrazole —SCH₂CH₃ CO Phenyl F,F Tetrazole —SCH₂CH₃ COPhenyl F,Cl Tetrazole —SCH₂CH₃ CO Phenyl Cl Tetrazole —SCH₂CH₃ CO PhenylCl,Cl Tetrazole —SCH₂CH₃ CO Phenyl -(1 to 4 linearly linked tetrazole—SCH₂CH₃ atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearlylinked tetrazole —SCH₂CH₃ atom linker)-optionally subst. heteroaryl COpyridinyl Tetrazole —SCH₂CH₃ CO Pyridinyl CF₃ Tetrazole —SCH₂CH₃ COPyridinyl CH₂CF₃ Tetrazole —SCH₂CH₃ CO Pyridinyl Halo substituted alkylTetrazole —SCH₂CH₃ CO Pyridinyl OCH₃ tetrazole —SCH₂CH₃ CO PyridinylOCH₂CH₃ tetrazole —SCH₂CH₃ CO Pyridinyl OCH₂CH₂CH₃ Tetrazole —SCH₂CH₃ COPyridinyl OCH₂CH₂CH₂CH₃ Tetrazole —SCH₂CH₃ CO Pyridinyl OCH₂CH₂CH₂CH₂CH₃Tetrazole —SCH₂CH₃ CO Pyridinyl C5-C8 alkoxy Tetrazole —SCH₂CH₃ COPyridinyl Halo substituted alkoxy tetrazole —SCH₂CH₃ CO Pyridinyl CH₃tetrazole —SCH₂CH₃ CO Pyridinyl CH₂CH₃ Tetrazole —SCH₂CH₃ CO PyridinylCH₂CH₂CH₃ Tetrazole —SCH₂CH₃ CO Pyridinyl CH₂CH₂CH₂CH₃ Tetrazole—SCH₂CH₃ CO Pyridinyl C5-C8 alkyl Tetrazole —SCH₂CH₃ CO Pyridinyl Ftetrazole —SCH₂CH₃ CO Pyridinyl F,F tetrazole —SCH₂CH₃ CO Pyridinyl F,ClTetrazole —SCH₂CH₃ CO Pyridinyl Cl Tetrazole —SCH₂CH₃ CO Pyridinyl Cl,ClTetrazole —SCH₂CH₃ CO Pyridinyl -(1 to 4 linearly linked Tetrazole—SCH₂CH₃ atom linker)-optionally subst. aryl CO Pyridinyl -(1 to 4linearly linked tetrazole —SCH₂CH₃ atom linker)-optionally subst.heteroaryl SO₂ phenyl 3-hydroxy isoxazole methoxy SO₂ phenyl CF₃3-hydroxy isoxazole methoxy SO₂ phenyl CH₂CF₃ 3-hydroxy isoxazolemethoxy SO₂ phenyl Halo substituted alkyl 3-hydroxy isoxazole methoxySO₂ phenyl OCH₃ 3-hydroxy isoxazole methoxy SO₂ phenyl OCH₂CH₃ 3-hydroxyisoxazole methoxy SO₂ phenyl OCH₂CH₂CH₃ 3-hydroxy isoxazole methoxy SO₂phenyl OCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole methoxy SO₂ phenylOCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole methoxy SO₂ phenyl C5-C8 alkoxy3-hydroxy isoxazole methoxy SO₂ phenyl Halo substituted alkoxy 3-hydroxyisoxazole methoxy SO₂ phenyl CH₃ 3-hydroxy isoxazole methoxy SO₂ phenylCH₂CH₃ 3-hydroxy isoxazole methoxy SO₂ phenyl CH₂CH₂CH₃ 3-hydroxyisoxazole methoxy SO₂ phenyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole methoxySO₂ phenyl C5-C8 alkyl 3-hydroxy isoxazole methoxy SO₂ phenyl F3-hydroxy isoxazole methoxy SO₂ phenyl F,F 3-hydroxy isoxazole methoxySO₂ phenyl F,Cl 3-hydroxy isoxazole methoxy SO₂ phenyl Cl 3-hydroxyisoxazole methoxy SO₂ phenyl Cl,Cl 3-hydroxy isoxazole methoxy SO₂phenyl -(1 to 4 linearly linked 3-hydroxy isoxazole methoxy atomlinker)-optionally subst. aryl SO₂ phenyl -(1 to 4 linearly linked3-hydroxy isoxazole methoxy atom linker)-optionally subst. heteroarylSO₂ pyridinyl 3-hydroxy isoxazole methoxy SO₂ Pyridinyl CF₃ 3-hydroxyisoxazole methoxy SO₂ Pyridinyl CH₂CF₃ 3-hydroxy isoxazole methoxy SO₂Pyridinyl Halo substituted alkyl 3-hydroxy isoxazole methoxy SO₂Pyridinyl OCH₃ 3-hydroxy isoxazole methoxy SO₂ Pyridinyl OCH₂CH₃3-hydroxy isoxazole methoxy SO₂ Pyridinyl OCH₂CH₂CH₃ 3-hydroxy isoxazolemethoxy SO₂ Pyridinyl OCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole methoxy SO₂Pyridinyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole methoxy SO₂ PyridinylC5-C8 alkoxy 3-hydroxy isoxazole methoxy SO₂ Pyridinyl Halo substitutedalkoxy 3-hydroxy isoxazole methoxy SO₂ Pyridinyl CH₃ 3-hydroxy isoxazolemethoxy SO₂ Pyridinyl CH₂CH₃ 3-hydroxy isoxazole methoxy SO₂ PyridinylCH₂CH₂CH₃ 3-hydroxy isoxazole methoxy SO₂ Pyridinyl CH₂CH₂CH₂CH₃3-hydroxy isoxazole methoxy SO₂ Pyridinyl C5-C8 alkyl 3-hydroxyisoxazole methoxy SO₂ Pyridinyl F 3-hydroxy isoxazole methoxy SO₂Pyridinyl F,F 3-hydroxy isoxazole methoxy SO₂ Pyridinyl F,Cl 3-hydroxyisoxazole methoxy SO₂ Pyridinyl Cl 3-hydroxy isoxazole methoxy SO₂Pyridinyl Cl,Cl 3-hydroxy isoxazole methoxy SO₂ Pyridinyl -(1 to 4linearly linked 3-hydroxy isoxazole methoxy atom linker)-optionallysubst. aryl SO₂ Pyridinyl -(1 to 4 linearly linked 3-hydroxy isoxazolemethoxy atom linker)-optionally subst. heteroaryl CO Phenyl 3-hydroxyisoxazole methoxy CO Phenyl CF₃ 3-hydroxy isoxazole methoxy CO PhenylCH₂CF₃ 3-hydroxy isoxazole methoxy CO Phenyl Halo substituted alkyl3-hydroxy isoxazole methoxy CO Phenyl OCH₃ 3-hydroxy isoxazole methoxyCO Phenyl OCH₂CH₃ 3-hydroxy isoxazole methoxy CO Phenyl OCH₂CH₂CH₃3-hydroxy isoxazole methoxy CO Phenyl OCH₂CH₂CH₂CH₃ 3-hydroxy isoxazolemethoxy CO Phenyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole methoxy CO PhenylC5-C8 alkoxy 3-hydroxy isoxazole methoxy CO Phenyl Halo substitutedalkoxy 3-hydroxy isoxazole methoxy CO Phenyl CH₃ 3-hydroxy isoxazolemethoxy CO Phenyl CH₂CH₃ 3-hydroxy isoxazole methoxy CO Phenyl CH₂CH₂CH₃3-hydroxy isoxazole methoxy CO Phenyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazolemethoxy CO Phenyl C5-C8 alkyl 3-hydroxy isoxazole methoxy CO Phenyl F3-hydroxy isoxazole methoxy CO Phenyl F,F 3-hydroxy isoxazole methoxy COPhenyl F,Cl 3-hydroxy isoxazole methoxy CO Phenyl Cl 3-hydroxy isoxazolemethoxy CO Phenyl Cl,Cl 3-hydroxy isoxazole methoxy CO Phenyl -(1 to 4linearly linked 3-hydroxy isoxazole methoxy atom linker)-optionallysubst. aryl CO Phenyl -(1 to 4 linearly linked 3-hydroxy isoxazolemethoxy atom linker)-optionally subst. heteroaryl CO pyridinyl 3-hydroxyisoxazole methoxy CO Pyridinyl CF₃ 3-hydroxy isoxazole methoxy COPyridinyl CH₂CF₃ 3-hydroxy isoxazole methoxy CO Pyridinyl Halosubstituted alkyl 3-hydroxy isoxazole methoxy CO Pyridinyl OCH₃3-hydroxy isoxazole methoxy CO Pyridinyl OCH₂CH₃ 3-hydroxy isoxazolemethoxy CO Pyridinyl OCH₂CH₂CH₃ 3-hydroxy isoxazole methoxy CO PyridinylOCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole methoxy CO Pyridinyl OCH₂CH₂CH₂CH₂CH₃3-hydroxy isoxazole methoxy CO Pyridinyl C5-C8 alkoxy 3-hydroxyisoxazole methoxy CO Pyridinyl Halo substituted alkoxy 3-hydroxyisoxazole methoxy CO Pyridinyl CH₃ 3-hydroxy isoxazole methoxy COPyridinyl CH₂CH₃ 3-hydroxy isoxazole methoxy CO Pyridinyl CH₂CH₂CH₃3-hydroxy isoxazole methoxy CO Pyridinyl CH₂CH₂CH₂CH₃ 3-hydroxyisoxazole methoxy CO Pyridinyl C5-C8 alkyl 3-hydroxy isoxazole methoxyCO Pyridinyl F 3-hydroxy isoxazole methoxy CO Pyridinyl F,F 3-hydroxyisoxazole methoxy CO Pyridinyl F,Cl 3-hydroxy isoxazole methoxy COPyridinyl Cl 3-hydroxy isoxazole methoxy CO Pyridinyl Cl,Cl 3-hydroxyisoxazole methoxy CO Pyridinyl -(1 to 4 linearly linked 3-hydroxyisoxazole methoxy atom linker)-optionally subst. aryl CO Pyridinyl -(1to 4 linearly linked 3-hydroxy isoxazole methoxy atom linker)-optionallysubst. heteroaryl SO₂ phenyl 3-hydroxy isoxazole ethoxy SO₂ phenyl CF₃3-hydroxy isoxazole ethoxy SO₂ phenyl CH₂CF₃ 3-hydroxy isoxazole ethoxySO₂ phenyl Halo substituted alkyl 3-hydroxy isoxazole ethoxy SO₂ phenylOCH₃ 3-hydroxy isoxazole ethoxy SO₂ phenyl OCH₂CH₃ 3-hydroxy isoxazoleethoxy SO₂ phenyl OCH₂CH₂CH₃ 3-hydroxy isoxazole ethoxy SO₂ phenylOCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole ethoxy SO₂ phenyl OCH₂CH₂CH₂CH₂CH₃3-hydroxy isoxazole ethoxy SO₂ phenyl C5-C8 alkoxy 3-hydroxy isoxazoleethoxy SO₂ phenyl Halo substituted alkoxy 3-hydroxy isoxazole ethoxy SO₂phenyl CH₃ 3-hydroxy isoxazole ethoxy SO₂ phenyl CH₂CH₃ 3-hydroxyisoxazole ethoxy SO₂ phenyl CH₂CH₂CH₃ 3-hydroxy isoxazole ethoxy SO₂phenyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole ethoxy SO₂ phenyl C5-C8 alkyl3-hydroxy isoxazole ethoxy SO₂ phenyl F 3-hydroxy isoxazole ethoxy SO₂phenyl F,F 3-hydroxy isoxazole ethoxy SO₂ phenyl F,Cl 3-hydroxyisoxazole ethoxy SO₂ phenyl Cl 3-hydroxy isoxazole ethoxy SO₂ phenylCl,Cl 3-hydroxy isoxazole ethoxy SO₂ phenyl -(1 to 4 linearly linked3-hydroxy isoxazole ethoxy atom linker)-optionally subst. aryl SO₂phenyl -(1 to 4 linearly linked 3-hydroxy isoxazole ethoxy atomlinker)-optionally subst. heteroaryl SO₂ pyridinyl 3-hydroxy isoxazoleethoxy SO₂ Pyridinyl CF₃ 3-hydroxy isoxazole ethoxy SO₂ Pyridinyl CH₂CF₃3-hydroxy isoxazole ethoxy SO₂ Pyridinyl Halo substituted alkyl3-hydroxy isoxazole ethoxy SO₂ Pyridinyl OCH₃ 3-hydroxy isoxazole ethoxySO₂ Pyridinyl OCH₂CH₃ 3-hydroxy isoxazole ethoxy SO₂ PyridinylOCH₂CH₂CH₃ 3-hydroxy isoxazole ethoxy SO₂ Pyridinyl OCH₂CH₂CH₂CH₃3-hydroxy isoxazole ethoxy SO₂ Pyridinyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxyisoxazole ethoxy SO₂ Pyridinyl C5-C8 alkoxy 3-hydroxy isoxazole ethoxySO₂ Pyridinyl Halo substituted alkoxy 3-hydroxy isoxazole ethoxy SO₂Pyridinyl CH₃ 3-hydroxy isoxazole ethoxy SO₂ Pyridinyl CH₂CH₃ 3-hydroxyisoxazole ethoxy SO₂ Pyridinyl CH₂CH₂CH₃ 3-hydroxy isoxazole ethoxy SO₂Pyridinyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole ethoxy SO₂ Pyridinyl C5-C8alkyl 3-hydroxy isoxazole ethoxy SO₂ Pyridinyl F 3-hydroxy isoxazoleethoxy SO₂ Pyridinyl F,F 3-hydroxy isoxazole ethoxy SO₂ Pyridinyl F,Cl3-hydroxy isoxazole ethoxy SO₂ Pyridinyl Cl 3-hydroxy isoxazole ethoxySO₂ Pyridinyl Cl,Cl 3-hydroxy isoxazole ethoxy SO₂ Pyridinyl -(1 to 4linearly linked 3-hydroxy isoxazole ethoxy atom linker)-optionallysubst. aryl SO₂ Pyridinyl -(1 to 4 linearly linked 3-hydroxy isoxazoleethoxy atom linker)-optionally subst. heteroaryl CO Phenyl 3-hydroxyisoxazole ethoxy CO Phenyl CF₃ 3-hydroxy isoxazole ethoxy CO PhenylCH₂CF₃ 3-hydroxy isoxazole ethoxy CO Phenyl Halo substituted alkyl3-hydroxy isoxazole ethoxy CO Phenyl OCH₃ 3-hydroxy isoxazole ethoxy COPhenyl OCH₂CH₃ 3-hydroxy isoxazole ethoxy CO Phenyl OCH₂CH₂CH₃ 3-hydroxyisoxazole ethoxy CO Phenyl OCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole ethoxy COPhenyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole ethoxy CO Phenyl C5-C8alkoxy 3-hydroxy isoxazole ethoxy CO Phenyl Halo substituted alkoxy3-hydroxy isoxazole ethoxy CO Phenyl CH₃ 3-hydroxy isoxazole ethoxy COPhenyl CH₂CH₃ 3-hydroxy isoxazole ethoxy CO Phenyl CH₂CH₂CH₃ 3-hydroxyisoxazole ethoxy CO Phenyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole ethoxy COPhenyl C5-C8 alkyl 3-hydroxy isoxazole ethoxy CO Phenyl F 3-hydroxyisoxazole ethoxy CO Phenyl F,F 3-hydroxy isoxazole ethoxy CO Phenyl F,Cl3-hydroxy isoxazole ethoxy CO Phenyl Cl 3-hydroxy isoxazole ethoxy COPhenyl Cl,Cl 3-hydroxy isoxazole ethoxy CO Phenyl -(1 to 4 linearlylinked 3-hydroxy isoxazole ethoxy atom linker)-optionally subst. aryl COPhenyl -(1 to 4 linearly linked 3-hydroxy isoxazole ethoxy atomlinker)-optionally subst. heteroaryl CO pyridinyl 3-hydroxy isoxazoleethoxy CO Pyridinyl CF₃ 3-hydroxy isoxazole ethoxy CO Pyridinyl CH₂CF₃3-hydroxy isoxazole ethoxy CO Pyridinyl Halo substituted alkyl 3-hydroxyisoxazole ethoxy CO Pyridinyl OCH₃ 3-hydroxy isoxazole ethoxy COPyridinyl OCH₂CH₃ 3-hydroxy isoxazole ethoxy CO Pyridinyl OCH₂CH₂CH₃3-hydroxy isoxazole ethoxy CO Pyridinyl OCH₂CH₂CH₂CH₃ 3-hydroxyisoxazole ethoxy CO Pyridinyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazoleethoxy CO Pyridinyl C5-C8 alkoxy 3-hydroxy isoxazole ethoxy CO PyridinylHalo substituted alkoxy 3-hydroxy isoxazole ethoxy CO Pyridinyl CH₃3-hydroxy isoxazole ethoxy CO Pyridinyl CH₂CH₃ 3-hydroxy isoxazoleethoxy CO Pyridinyl CH₂CH₂CH₃ 3-hydroxy isoxazole ethoxy CO PyridinylCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole ethoxy CO Pyridinyl C5-C8 alkyl3-hydroxy isoxazole ethoxy CO Pyridinyl F 3-hydroxy isoxazole ethoxy COPyridinyl F,F 3-hydroxy isoxazole ethoxy CO Pyridinyl F,Cl 3-hydroxyisoxazole ethoxy CO Pyridinyl Cl 3-hydroxy isoxazole ethoxy CO PyridinylCl,Cl 3-hydroxy isoxazole ethoxy CO Pyridinyl -(1 to 4 linearly linked3-hydroxy isoxazole ethoxy atom linker)-optionally subst. aryl COPyridinyl -(1 to 4 linearly linked 3-hydroxy isoxazole ethoxy atomlinker)-optionally subst. heteroaryl SO₂ phenyl 3-hydroxy isoxazolepropoxy SO₂ phenyl CF₃ 3-hydroxy isoxazole propoxy SO₂ phenyl CH₂CF₃3-hydroxy isoxazole propoxy SO₂ phenyl Halo substituted alkyl 3-hydroxyisoxazole propoxy SO₂ phenyl OCH₃ 3-hydroxy isoxazole propoxy SO₂ phenylOCH₂CH₃ 3-hydroxy isoxazole propoxy SO₂ phenyl OCH₂CH₂CH₃ 3-hydroxyisoxazole propoxy SO₂ phenyl OCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole propoxySO₂ phenyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole propoxy SO₂ phenyl C5-C8alkoxy 3-hydroxy isoxazole propoxy SO₂ phenyl Halo substituted alkoxy3-hydroxy isoxazole propoxy SO₂ phenyl CH₃ 3-hydroxy isoxazole propoxySO₂ phenyl CH₂CH₃ 3-hydroxy isoxazole propoxy SO₂ phenyl CH₂CH₂CH₃3-hydroxy isoxazole propoxy SO₂ phenyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazolepropoxy SO₂ phenyl C5-C8 alkyl 3-hydroxy isoxazole propoxy SO₂ phenyl F3-hydroxy isoxazole propoxy SO₂ phenyl F,F 3-hydroxy isoxazole propoxySO₂ phenyl F,Cl 3-hydroxy isoxazole propoxy SO₂ phenyl Cl 3-hydroxyisoxazole propoxy SO₂ phenyl Cl,Cl 3-hydroxy isoxazole propoxy SO₂phenyl -(1 to 4 linearly linked 3-hydroxy isoxazole propoxy atomlinker)-optionally subst. aryl SO₂ phenyl -(1 to 4 linearly linked3-hydroxy isoxazole propoxy atom linker)-optionally subst. heteroarylSO₂ pyridinyl 3-hydroxy isoxazole propoxy SO₂ Pyridinyl CF₃ 3-hydroxyisoxazole propoxy SO₂ Pyridinyl CH₂CF₃ 3-hydroxy isoxazole propoxy SO₂Pyridinyl Halo substituted alkyl 3-hydroxy isoxazole propoxy SO₂Pyridinyl OCH₃ 3-hydroxy isoxazole propoxy SO₂ Pyridinyl OCH₂CH₃3-hydroxy isoxazole propoxy SO₂ Pyridinyl OCH₂CH₂CH₃ 3-hydroxy isoxazolepropoxy SO₂ Pyridinyl OCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole propoxy SO₂Pyridinyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole propoxy SO₂ PyridinylC5-C8 alkoxy 3-hydroxy isoxazole propoxy SO₂ Pyridinyl Halo substitutedalkoxy 3-hydroxy isoxazole propoxy SO₂ Pyridinyl CH₃ 3-hydroxy isoxazolepropoxy SO₂ Pyridinyl CH₂CH₃ 3-hydroxy isoxazole propoxy SO₂ PyridinylCH₂CH₂CH₃ 3-hydroxy isoxazole propoxy SO₂ Pyridinyl CH₂CH₂CH₂CH₃3-hydroxy isoxazole propoxy SO₂ Pyridinyl C5-C8 alkyl 3-hydroxyisoxazole propoxy SO₂ Pyridinyl F 3-hydroxy isoxazole propoxy SO₂Pyridinyl F,F 3-hydroxy isoxazole propoxy SO₂ Pyridinyl F,Cl 3-hydroxyisoxazole propoxy SO₂ Pyridinyl Cl 3-hydroxy isoxazole propoxy SO₂Pyridinyl Cl,Cl 3-hydroxy isoxazole propoxy SO₂ Pyridinyl -(1 to 4linearly linked 3-hydroxy isoxazole propoxy atom linker)-optionallysubst. aryl SO₂ Pyridinyl -(1 to 4 linearly linked 3-hydroxy isoxazolepropoxy atom linker)-optionally subst. heteroaryl CO Phenyl 3-hydroxyisoxazole propoxy CO Phenyl CF₃ 3-hydroxy isoxazole propoxy CO PhenylCH₂CF₃ 3-hydroxy isoxazole propoxy CO Phenyl Halo substituted alkyl3-hydroxy isoxazole propoxy CO Phenyl OCH₃ 3-hydroxy isoxazole propoxyCO Phenyl OCH₂CH₃ 3-hydroxy isoxazole propoxy CO Phenyl OCH₂CH₂CH₃3-hydroxy isoxazole propoxy CO Phenyl OCH₂CH₂CH₂CH₃ 3-hydroxy isoxazolepropoxy CO Phenyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole propoxy CO PhenylC5-C8 alkoxy 3-hydroxy isoxazole propoxy CO Phenyl Halo substitutedalkoxy 3-hydroxy isoxazole propoxy CO Phenyl CH₃ 3-hydroxy isoxazolepropoxy CO Phenyl CH₂CH₃ 3-hydroxy isoxazole propoxy CO Phenyl CH₂CH₂CH₃3-hydroxy isoxazole propoxy CO Phenyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazolepropoxy CO Phenyl C5-C8 alkyl 3-hydroxy isoxazole propoxy CO Phenyl F3-hydroxy isoxazole propoxy CO Phenyl F,F 3-hydroxy isoxazole propoxy COPhenyl F,Cl 3-hydroxy isoxazole propoxy CO Phenyl Cl 3-hydroxy isoxazolepropoxy CO Phenyl Cl,Cl 3-hydroxy isoxazole propoxy CO Phenyl -(1 to 4linearly linked 3-hydroxy isoxazole propoxy atom linker)-optionallysubst. aryl CO Phenyl -(1 to 4 linearly linked 3-hydroxy isoxazolepropoxy atom linker)-optionally subst. heteroaryl CO pyridinyl 3-hydroxyisoxazole propoxy CO Pyridinyl CF₃ 3-hydroxy isoxazole propoxy COPyridinyl CH₂CF₃ 3-hydroxy isoxazole propoxy CO Pyridinyl Halosubstituted alkyl 3-hydroxy isoxazole propoxy CO Pyridinyl OCH₃3-hydroxy isoxazole propoxy CO Pyridinyl OCH₂CH₃ 3-hydroxy isoxazolepropoxy CO Pyridinyl OCH₂CH₂CH₃ 3-hydroxy isoxazole propoxy CO PyridinylOCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole propoxy CO Pyridinyl OCH₂CH₂CH₂CH₂CH₃3-hydroxy isoxazole propoxy CO Pyridinyl C5-C8 alkoxy 3-hydroxyisoxazole propoxy CO Pyridinyl Halo substituted alkoxy 3-hydroxyisoxazole propoxy CO Pyridinyl CH₃ 3-hydroxy isoxazole propoxy COPyridinyl CH₂CH₃ 3-hydroxy isoxazole propoxy CO Pyridinyl CH₂CH₂CH₃3-hydroxy isoxazole propoxy CO Pyridinyl CH₂CH₂CH₂CH₃ 3-hydroxyisoxazole propoxy CO Pyridinyl C5-C8 alkyl 3-hydroxy isoxazole propoxyCO Pyridinyl F 3-hydroxy isoxazole propoxy CO Pyridinyl F,F 3-hydroxyisoxazole propoxy CO Pyridinyl F,Cl 3-hydroxy isoxazole propoxy COPyridinyl Cl 3-hydroxy isoxazole propoxy CO Pyridinyl Cl,Cl 3-hydroxyisoxazole propoxy CO Pyridinyl -(1 to 4 linearly linked 3-hydroxyisoxazole propoxy atom linker)-optionally subst. aryl CO Pyridinyl -(1to 4 linearly linked 3-hydroxy isoxazole propoxy atom linker)-optionallysubst. heteroaryl SO₂ phenyl 3-hydroxy isoxazole —SCH₃ SO₂ phenyl CF₃3-hydroxy isoxazole —SCH₃ SO₂ phenyl CH₂CF₃ 3-hydroxy isoxazole —SCH₃SO₂ phenyl Halo substituted alkyl 3-hydroxy isoxazole —SCH₃ SO₂ phenylOCH₃ 3-hydroxy isoxazole —SCH₃ SO₂ phenyl OCH₂CH₃ 3-hydroxy isoxazole—SCH₃ SO₂ phenyl OCH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₃ SO₂ phenylOCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₃ SO₂ phenyl OCH₂CH₂CH₂CH₂CH₃3-hydroxy isoxazole —SCH₃ SO₂ phenyl C5-C8 alkoxy 3-hydroxy isoxazole—SCH₃ SO₂ phenyl Halo substituted alkoxy 3-hydroxy isoxazole —SCH₃ SO₂phenyl CH₃ 3-hydroxy isoxazole —SCH₃ SO₂ phenyl CH₂CH₃ 3-hydroxyisoxazole —SCH₃ SO₂ phenyl CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₃ SO₂phenyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₃ SO₂ phenyl C5-C8 alkyl3-hydroxy isoxazole —SCH₃ SO₂ phenyl F 3-hydroxy isoxazole —SCH₃ SO₂phenyl F,F 3-hydroxy isoxazole —SCH₃ SO₂ phenyl F,Cl 3-hydroxy isoxazole—SCH₃ SO₂ phenyl Cl 3-hydroxy isoxazole —SCH₃ SO₂ phenyl Cl,Cl 3-hydroxyisoxazole —SCH₃ SO₂ phenyl -(1 to 4 linearly linked 3-hydroxy isoxazole—SCH₃ atom linker)-optionally subst. aryl SO₂ phenyl -(1 to 4 linearlylinked 3-hydroxy isoxazole —SCH₃ atom linker)-optionally subst.heteroaryl SO₂ pyridinyl 3-hydroxy isoxazole —SCH₃ SO₂ Pyridinyl CF₃3-hydroxy isoxazole —SCH₃ SO₂ Pyridinyl CH₂CF₃ 3-hydroxy isoxazole —SCH₃SO₂ Pyridinyl Halo substituted alkyl 3-hydroxy isoxazole —SCH₃ SO₂Pyridinyl OCH₃ 3-hydroxy isoxazole —SCH₃ SO₂ Pyridinyl OCH₂CH₃ 3-hydroxyisoxazole —SCH₃ SO₂ Pyridinyl OCH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₃ SO₂Pyridinyl OCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₃ SO₂ PyridinylOCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₃ SO₂ Pyridinyl C5-C8 alkoxy3-hydroxy isoxazole —SCH₃ SO₂ Pyridinyl Halo substituted alkoxy3-hydroxy isoxazole —SCH₃ SO₂ Pyridinyl CH₃ 3-hydroxy isoxazole —SCH₃SO₂ Pyridinyl CH₂CH₃ 3-hydroxy isoxazole —SCH₃ SO₂ Pyridinyl CH₂CH₂CH₃3-hydroxy isoxazole —SCH₃ SO₂ Pyridinyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole—SCH₃ SO₂ Pyridinyl C5-C8 alkyl 3-hydroxy isoxazole —SCH₃ SO₂ PyridinylF 3-hydroxy isoxazole —SCH₃ SO₂ Pyridinyl F,F 3-hydroxy isoxazole —SCH₃SO₂ Pyridinyl F,Cl 3-hydroxy isoxazole —SCH₃ SO₂ Pyridinyl Cl 3-hydroxyisoxazole —SCH₃ SO₂ Pyridinyl Cl,Cl 3-hydroxy isoxazole —SCH₃ SO₂Pyridinyl -(1 to 4 linearly linked 3-hydroxy isoxazole —SCH₃ atomlinker)-optionally subst. aryl SO₂ Pyridinyl -(1 to 4 linearly linked3-hydroxy isoxazole —SCH₃ atom linker)-optionally subst. heteroaryl COPhenyl 3-hydroxy isoxazole —SCH₃ CO Phenyl CF₃ 3-hydroxy isoxazole —SCH₃CO Phenyl CH₂CF₃ 3-hydroxy isoxazole —SCH₃ CO Phenyl Halo substitutedalkyl 3-hydroxy isoxazole —SCH₃ CO Phenyl OCH₃ 3-hydroxy isoxazole —SCH₃CO Phenyl OCH₂CH₃ 3-hydroxy isoxazole —SCH₃ CO Phenyl OCH₂CH₂CH₃3-hydroxy isoxazole —SCH₃ CO Phenyl OCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole—SCH₃ CO Phenyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₃ CO PhenylC5-C8 alkoxy 3-hydroxy isoxazole —SCH₃ CO Phenyl Halo substituted alkoxy3-hydroxy isoxazole —SCH₃ CO Phenyl CH₃ 3-hydroxy isoxazole —SCH₃ COPhenyl CH₂CH₃ 3-hydroxy isoxazole —SCH₃ CO Phenyl CH₂CH₂CH₃ 3-hydroxyisoxazole —SCH₃ CO Phenyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₃ COPhenyl C5-C8 alkyl 3-hydroxy isoxazole —SCH₃ CO Phenyl F 3-hydroxyisoxazole —SCH₃ CO Phenyl F,F 3-hydroxy isoxazole —SCH₃ CO Phenyl F,Cl3-hydroxy isoxazole —SCH₃ CO Phenyl Cl 3-hydroxy isoxazole —SCH₃ COPhenyl Cl,Cl 3-hydroxy isoxazole —SCH₃ CO Phenyl -(1 to 4 linearlylinked 3-hydroxy isoxazole —SCH₃ atom linker)-optionally subst. aryl COPhenyl -(1 to 4 linearly linked 3-hydroxy isoxazole —SCH₃ atomlinker)-optionally subst. heteroaryl CO pyridinyl 3-hydroxy isoxazole—SCH₃ CO Pyridinyl CF₃ 3-hydroxy isoxazole —SCH₃ CO Pyridinyl CH₂CF₃3-hydroxy isoxazole —SCH₃ CO Pyridinyl Halo substituted alkyl 3-hydroxyisoxazole —SCH₃ CO Pyridinyl OCH₃ 3-hydroxy isoxazole —SCH₃ CO PyridinylOCH₂CH₃ 3-hydroxy isoxazole —SCH₃ CO Pyridinyl OCH₂CH₂CH₃ 3-hydroxyisoxazole —SCH₃ CO Pyridinyl OCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₃ COPyridinyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₃ CO Pyridinyl C5-C8alkoxy 3-hydroxy isoxazole —SCH₃ CO Pyridinyl Halo substituted alkoxy3-hydroxy isoxazole —SCH₃ CO Pyridinyl CH₃ 3-hydroxy isoxazole —SCH₃ COPyridinyl CH₂CH₃ 3-hydroxy isoxazole —SCH₃ CO Pyridinyl CH₂CH₂CH₃3-hydroxy isoxazole —SCH₃ CO Pyridinyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole—SCH₃ CO Pyridinyl C5-C8 alkyl 3-hydroxy isoxazole —SCH₃ CO Pyridinyl F3-hydroxy isoxazole —SCH₃ CO Pyridinyl F,F 3-hydroxy isoxazole —SCH₃ COPyridinyl F,Cl 3-hydroxy isoxazole —SCH₃ CO Pyridinyl Cl 3-hydroxyisoxazole —SCH₃ CO Pyridinyl Cl,Cl 3-hydroxy isoxazole —SCH₃ COPyridinyl -(1 to 4 linearly linked 3-hydroxy isoxazole —SCH₃ atomlinker)-optionally subst. aryl CO Pyridinyl -(1 to 4 linearly linked3-hydroxy isoxazole —SCH₃ atom linker)-optionally subst. heteroaryl SO₂phenyl 3-hydroxy isoxazole —SCH₂CH₃ SO₂ phenyl CF₃ 3-hydroxy isoxazole—SCH₂CH₃ SO₂ phenyl CH₂CF₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂ phenyl Halosubstituted alkyl 3-hydroxy isoxazole —SCH₂CH₃ SO₂ phenyl OCH₃ 3-hydroxyisoxazole —SCH₂CH₃ SO₂ phenyl OCH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂phenyl OCH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂ phenyl OCH₂CH₂CH₂CH₃3-hydroxy isoxazole —SCH₂CH₃ SO₂ phenyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxyisoxazole —SCH₂CH₃ SO₂ phenyl C5-C8 alkoxy 3-hydroxy isoxazole —SCH₂CH₃SO₂ phenyl Halo substituted alkoxy 3-hydroxy isoxazole —SCH₂CH₃ SO₂phenyl CH₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂ phenyl CH₂CH₃ 3-hydroxyisoxazole —SCH₂CH₃ SO₂ phenyl CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂phenyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂ phenyl C5-C8 alkyl3-hydroxy isoxazole —SCH₂CH₃ SO₂ phenyl F 3-hydroxy isoxazole —SCH₂CH₃SO₂ phenyl F,F 3-hydroxy isoxazole —SCH₂CH₃ SO₂ phenyl F,Cl 3-hydroxyisoxazole —SCH₂CH₃ SO₂ phenyl Cl 3-hydroxy isoxazole —SCH₂CH₃ SO₂ phenylCl,Cl 3-hydroxy isoxazole —SCH₂CH₃ SO₂ phenyl -(1 to 4 linearly linked3-hydroxy isoxazole —SCH₂CH₃ atom linker)-optionally subst. aryl SO₂phenyl -(1 to 4 linearly linked 3-hydroxy isoxazole —SCH₂CH₃ atomlinker)-optionally subst. heteroaryl SO₂ pyridinyl 3-hydroxy isoxazole—SCH₂CH₃ SO₂ Pyridinyl CF₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂ PyridinylCH₂CF₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂ Pyridinyl Halo substituted alkyl3-hydroxy isoxazole —SCH₂CH₃ SO₂ Pyridinyl OCH₃ 3-hydroxy isoxazole—SCH₂CH₃ SO₂ Pyridinyl OCH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂Pyridinyl OCH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂ PyridinylOCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂ PyridinylOCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂ Pyridinyl C5-C8 alkoxy3-hydroxy isoxazole —SCH₂CH₃ SO₂ Pyridinyl Halo substituted alkoxy3-hydroxy isoxazole —SCH₂CH₃ SO₂ Pyridinyl CH₃ 3-hydroxy isoxazole—SCH₂CH₃ SO₂ Pyridinyl CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂ PyridinylCH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂ Pyridinyl CH₂CH₂CH₂CH₃3-hydroxy isoxazole —SCH₂CH₃ SO₂ Pyridinyl C5-C8 alkyl 3-hydroxyisoxazole —SCH₂CH₃ SO₂ Pyridinyl F 3-hydroxy isoxazole —SCH₂CH₃ SO₂Pyridinyl F,F 3-hydroxy isoxazole —SCH₂CH₃ SO₂ Pyridinyl F,Cl 3-hydroxyisoxazole —SCH₂CH₃ SO₂ Pyridinyl Cl 3-hydroxy isoxazole —SCH₂CH₃ SO₂Pyridinyl Cl,Cl 3-hydroxy isoxazole —SCH₂CH₃ SO₂ Pyridinyl -(1 to 4linearly linked 3-hydroxy isoxazole —SCH₂CH₃ atom linker)-optionallysubst. aryl SO₂ Pyridinyl -(1 to 4 linearly linked 3-hydroxy isoxazole—SCH₂CH₃ atom linker)-optionally subst. heteroaryl CO Phenyl 3-hydroxyisoxazole —SCH₂CH₃ CO Phenyl CF₃ 3-hydroxy isoxazole —SCH₂CH₃ CO PhenylCH₂CF₃ 3-hydroxy isoxazole —SCH₂CH₃ CO Phenyl Halo substituted alkyl3-hydroxy isoxazole —SCH₂CH₃ CO Phenyl OCH₃ 3-hydroxy isoxazole —SCH₂CH₃CO Phenyl OCH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ CO Phenyl OCH₂CH₂CH₃3-hydroxy isoxazole —SCH₂CH₃ CO Phenyl OCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole—SCH₂CH₃ CO Phenyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ COPhenyl C5-C8 alkoxy 3-hydroxy isoxazole —SCH₂CH₃ CO Phenyl Halosubstituted alkoxy 3-hydroxy isoxazole —SCH₂CH₃ CO Phenyl CH₃ 3-hydroxyisoxazole —SCH₂CH₃ CO Phenyl CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ COPhenyl CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ CO Phenyl CH₂CH₂CH₂CH₃3-hydroxy isoxazole —SCH₂CH₃ CO Phenyl C5-C8 alkyl 3-hydroxy isoxazole—SCH₂CH₃ CO Phenyl F 3-hydroxy isoxazole —SCH₂CH₃ CO Phenyl F,F3-hydroxy isoxazole —SCH₂CH₃ CO Phenyl F,Cl 3-hydroxy isoxazole —SCH₂CH₃CO Phenyl Cl 3-hydroxy isoxazole —SCH₂CH₃ CO Phenyl Cl,Cl 3-hydroxyisoxazole —SCH₂CH₃ CO Phenyl -(1 to 4 linearly linked 3-hydroxyisoxazole —SCH₂CH₃ atom linker)-optionally subst. aryl CO Phenyl -(1 to4 linearly linked 3-hydroxy isoxazole —SCH₂CH₃ atom linker)-optionallysubst. heteroaryl CO pyridinyl 3-hydroxy isoxazole —SCH₂CH₃ CO PyridinylCF₃ 3-hydroxy isoxazole —SCH₂CH₃ CO Pyridinyl CH₂CF₃ 3-hydroxy isoxazole—SCH₂CH₃ CO Pyridinyl Halo substituted alkyl 3-hydroxy isoxazole—SCH₂CH₃ CO Pyridinyl OCH₃ 3-hydroxy isoxazole —SCH₂CH₃ CO PyridinylOCH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ CO Pyridinyl OCH₂CH₂CH₃ 3-hydroxyisoxazole —SCH₂CH₃ CO Pyridinyl OCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole—SCH₂CH₃ CO Pyridinyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ COPyridinyl C5-C8 alkoxy 3-hydroxy isoxazole —SCH₂CH₃ CO Pyridinyl Halosubstituted alkoxy 3-hydroxy isoxazole —SCH₂CH₃ CO Pyridinyl CH₃3-hydroxy isoxazole —SCH₂CH₃ CO Pyridinyl CH₂CH₃ 3-hydroxy isoxazole—SCH₂CH₃ CO Pyridinyl CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ COPyridinyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ CO Pyridinyl C5-C8alkyl 3-hydroxy isoxazole —SCH₂CH₃ CO Pyridinyl F 3-hydroxy isoxazole—SCH₂CH₃ CO Pyridinyl F,F 3-hydroxy isoxazole —SCH₂CH₃ CO Pyridinyl F,Cl3-hydroxy isoxazole —SCH₂CH₃ CO Pyridinyl Cl 3-hydroxy isoxazole—SCH₂CH₃ CO Pyridinyl Cl,Cl 3-hydroxy isoxazole —SCH₂CH₃ CO Pyridinyl-(1 to 4 linearly linked 3-hydroxy isoxazole —SCH₂CH₃ atomlinker)-optionally subst. aryl CO Pyridinyl -(1 to 4 linearly linked3-hydroxy isoxazole —SCH₂CH₃ atom linker)-optionally subst. heteroarylSO₂ phenyl COOH methoxy SO₂ phenyl CF₃ COOH methoxy SO₂ phenyl CH₂CF₃COOH methoxy SO₂ phenyl Halo substituted alkyl COOH methoxy SO₂ phenylOCH₃ COOH methoxy SO₂ phenyl OCH₂CH₃ COOH methoxy SO₂ phenyl OCH₂CH₂CH₃COOH methoxy SO₂ phenyl OCH₂CH₂CH₂CH₃ COOH methoxy SO₂ phenylOCH₂CH₂CH₂CH₂CH₃ COOH methoxy SO₂ phenyl C5-C8 alkoxy COOH methoxy SO₂phenyl Halo substituted alkoxy COOH methoxy SO₂ phenyl CH₃ COOH methoxySO₂ phenyl CH₂CH₃ COOH methoxy SO₂ phenyl CH₂CH₂CH₃ COOH methoxy SO₂phenyl CH₂CH₂CH₂CH₃ COOH methoxy SO₂ phenyl C5-C8 alkyl COOH methoxy SO₂phenyl F COOH methoxy SO₂ phenyl F,F COOH methoxy SO₂ phenyl F,Cl COOHmethoxy SO₂ phenyl Cl COOH methoxy SO₂ phenyl Cl,Cl COOH methoxy SO₂phenyl -(1 to 4 linearly linked COOH methoxy atom linker)-optionallysubst. aryl SO₂ phenyl -(1 to 4 linearly linked COOH methoxy atomlinker)-optionally subst. heteroaryl SO₂ pyridinyl COOH methoxy SO₂Pyridinyl CF₃ COOH methoxy SO₂ Pyridinyl CH₂CF₃ COOH methoxy SO₂Pyridinyl Halo substituted alkyl COOH methoxy SO₂ Pyridinyl OCH₃ COOHmethoxy SO₂ Pyridinyl OCH₂CH₃ COOH methoxy SO₂ Pyridinyl OCH₂CH₂CH₃ COOHmethoxy SO₂ Pyridinyl OCH₂CH₂CH₂CH₃ COOH methoxy SO₂ PyridinylOCH₂CH₂CH₂CH₂CH₃ COOH methoxy SO₂ Pyridinyl C5-C8 alkoxy COOH methoxySO₂ Pyridinyl Halo substituted alkoxy COOH methoxy SO₂ Pyridinyl CH₃COOH methoxy SO₂ Pyridinyl CH₂CH₃ COOH methoxy SO₂ Pyridinyl CH₂CH₂CH₃COOH methoxy SO₂ Pyridinyl CH₂CH₂CH₂CH₃ COOH methoxy SO₂ Pyridinyl C5-C8alkyl COOH methoxy SO₂ Pyridinyl F COOH methoxy SO₂ Pyridinyl F,F COOHmethoxy SO₂ Pyridinyl F,Cl COOH methoxy SO₂ Pyridinyl Cl COOH methoxySO₂ Pyridinyl Cl,Cl COOH methoxy SO₂ Pyridinyl -(1 to 4 linearly linkedCOOH methoxy atom linker)-optionally subst. aryl SO₂ Pyridinyl -(1 to 4linearly linked COOH methoxy atom linker)-optionally subst. heteroarylCO Phenyl COOH methoxy CO Phenyl CF₃ COOH methoxy CO Phenyl CH₂CF₃ COOHmethoxy CO Phenyl Halo substituted alkyl COOH methoxy CO Phenyl OCH₃COOH methoxy CO Phenyl OCH₂CH₃ COOH methoxy CO Phenyl OCH₂CH₂CH₃ COOHmethoxy CO Phenyl OCH₂CH₂CH₂CH₃ COOH methoxy CO Phenyl OCH₂CH₂CH₂CH₂CH₃COOH methoxy CO Phenyl C5-C8 alkoxy COOH methoxy CO Phenyl Halosubstituted alkoxy COOH methoxy CO Phenyl CH₃ COOH methoxy CO PhenylCH₂CH₃ COOH methoxy CO Phenyl CH₂CH₂CH₃ COOH methoxy CO PhenylCH₂CH₂CH₂CH₃ COOH methoxy CO Phenyl C5-C8 alkyl COOH methoxy CO Phenyl FCOOH methoxy CO Phenyl F,F COOH methoxy CO Phenyl F,Cl COOH methoxy COPhenyl Cl COOH methoxy CO Phenyl Cl,Cl COOH methoxy CO Phenyl -(1 to 4linearly linked COOH methoxy atom linker)-optionally subst. aryl COPhenyl -(1 to 4 linearly linked COOH methoxy atom linker)-optionallysubst. heteroaryl CO pyridinyl COOH methoxy CO Pyridinyl CF₃ COOHmethoxy CO Pyridinyl CH₂CF₃ COOH methoxy CO Pyridinyl Halo substitutedalkyl COOH methoxy CO Pyridinyl OCH₃ COOH methoxy CO Pyridinyl OCH₂CH₃COOH methoxy CO Pyridinyl OCH₂CH₂CH₃ COOH methoxy CO PyridinylOCH₂CH₂CH₂CH₃ COOH methoxy CO Pyridinyl OCH₂CH₂CH₂CH₂CH₃ COOH methoxy COPyridinyl C5-C8 alkoxy COOH methoxy CO Pyridinyl Halo substituted alkoxyCOOH methoxy CO Pyridinyl CH₃ COOH methoxy CO Pyridinyl CH₂CH₃ COOHmethoxy CO Pyridinyl CH₂CH₂CH₃ COOH methoxy CO Pyridinyl CH₂CH₂CH₂CH₃COOH methoxy CO Pyridinyl C5-C8 alkyl COOH methoxy CO Pyridinyl F COOHmethoxy CO Pyridinyl F,F COOH methoxy CO Pyridinyl F,Cl COOH methoxy COPyridinyl Cl COOH methoxy CO Pyridinyl Cl,Cl COOH methoxy CO Pyridinyl-(1 to 4 linearly linked COOH methoxy atom linker)-optionally subst.aryl CO Pyridinyl -(1 to 4 linearly linked COOH methoxy atomlinker)-optionally subst. heteroaryl SO₂ phenyl COOH ethoxy SO₂ phenylCF₃ COOH ethoxy SO₂ phenyl CH₂CF₃ COOH ethoxy SO₂ phenyl Halosubstituted alkyl COOH ethoxy SO₂ phenyl OCH₃ COOH ethoxy SO₂ phenylOCH₂CH₃ COOH ethoxy SO₂ phenyl OCH₂CH₂CH₃ COOH ethoxy SO₂ phenylOCH₂CH₂CH₂CH₃ COOH ethoxy SO₂ phenyl OCH₂CH₂CH₂CH₂CH₃ COOH ethoxy SO₂phenyl C5-C8 alkoxy COOH ethoxy SO₂ phenyl Halo substituted alkoxy COOHethoxy SO₂ phenyl CH₃ COOH ethoxy SO₂ phenyl CH₂CH₃ COOH ethoxy SO₂phenyl CH₂CH₂CH₃ COOH ethoxy SO₂ phenyl CH₂CH₂CH₂CH₃ COOH ethoxy SO₂phenyl C5-C8 alkyl COOH ethoxy SO₂ phenyl F COOH ethoxy SO₂ phenyl F,FCOOH ethoxy SO₂ phenyl F,Cl COOH ethoxy SO₂ phenyl Cl COOH ethoxy SO₂phenyl Cl,Cl COOH ethoxy SO₂ phenyl -(1 to 4 linearly linked COOH ethoxyatom linker)-optionally subst. aryl SO₂ phenyl -(1 to 4 linearly linkedCOOH ethoxy atom linker)-optionally subst. heteroaryl SO₂ pyridinyl COOHethoxy SO₂ Pyridinyl CF₃ COOH ethoxy SO₂ Pyridinyl CH₂CF₃ COOH ethoxySO₂ Pyridinyl Halo substituted alkyl COOH ethoxy SO₂ Pyridinyl OCH₃ COOHethoxy SO₂ Pyridinyl OCH₂CH₃ COOH ethoxy SO₂ Pyridinyl OCH₂CH₂CH₃ COOHethoxy SO₂ Pyridinyl OCH₂CH₂CH₂CH₃ COOH ethoxy SO₂ PyridinylOCH₂CH₂CH₂CH₂CH₃ COOH ethoxy SO₂ Pyridinyl C5-C8 alkoxy COOH ethoxy SO₂Pyridinyl Halo substituted alkoxy COOH ethoxy SO₂ Pyridinyl CH₃ COOHethoxy SO₂ Pyridinyl CH₂CH₃ COOH ethoxy SO₂ Pyridinyl CH₂CH₂CH₃ COOHethoxy SO₂ Pyridinyl CH₂CH₂CH₂CH₃ COOH ethoxy SO₂ Pyridinyl C5-C8 alkylCOOH ethoxy SO₂ Pyridinyl F COOH ethoxy SO₂ Pyridinyl F,F COOH ethoxySO₂ Pyridinyl F,Cl COOH ethoxy SO₂ Pyridinyl Cl COOH ethoxy SO₂Pyridinyl Cl,Cl COOH ethoxy SO₂ Pyridinyl -(1 to 4 linearly linked COOHethoxy atom linker)-optionally subst. aryl SO₂ Pyridinyl -(1 to 4linearly linked COOH ethoxy atom linker)-optionally subst. heteroaryl COPhenyl COOH ethoxy CO Phenyl CF₃ COOH ethoxy CO Phenyl CH₂CF₃ COOHethoxy CO Phenyl Halo substituted alkyl COOH ethoxy CO Phenyl OCH₃ COOHethoxy CO Phenyl OCH₂CH₃ COOH ethoxy CO Phenyl OCH₂CH₂CH₃ COOH ethoxy COPhenyl OCH₂CH₂CH₂CH₃ COOH ethoxy CO Phenyl OCH₂CH₂CH₂CH₂CH₃ COOH ethoxyCO Phenyl C5-C8 alkoxy COOH ethoxy CO Phenyl Halo substituted alkoxyCOOH ethoxy CO Phenyl CH₃ COOH ethoxy CO Phenyl CH₂CH₃ COOH ethoxy COPhenyl CH₂CH₂CH₃ COOH ethoxy CO Phenyl CH₂CH₂CH₂CH₃ COOH ethoxy COPhenyl C5-C8 alkyl COOH ethoxy CO Phenyl F COOH ethoxy CO Phenyl F,FCOOH ethoxy CO Phenyl F,Cl COOH ethoxy CO Phenyl Cl COOH ethoxy COPhenyl Cl,Cl COOH ethoxy CO Phenyl -(1 to 4 linearly linked COOH ethoxyatom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearly linkedCOOH ethoxy atom linker)-optionally subst. heteroaryl CO pyridinyl COOHethoxy CO Pyridinyl CF₃ COOH ethoxy CO Pyridinyl CH₂CF₃ COOH ethoxy COPyridinyl Halo substituted alkyl COOH ethoxy CO Pyridinyl OCH₃ COOHethoxy CO Pyridinyl OCH₂CH₃ COOH ethoxy CO Pyridinyl OCH₂CH₂CH₃ COOHethoxy CO Pyridinyl OCH₂CH₂CH₂CH₃ COOH ethoxy CO PyridinylOCH₂CH₂CH₂CH₂CH₃ COOH ethoxy CO Pyridinyl C5-C8 alkoxy COOH ethoxy COPyridinyl Halo substituted alkoxy COOH ethoxy CO Pyridinyl CH₃ COOHethoxy CO Pyridinyl CH₂CH₃ COOH ethoxy CO Pyridinyl CH₂CH₂CH₃ COOHethoxy CO Pyridinyl CH₂CH₂CH₂CH₃ COOH ethoxy CO Pyridinyl C5-C8 alkylCOOH ethoxy CO Pyridinyl F COOH ethoxy CO Pyridinyl F,F COOH ethoxy COPyridinyl F,Cl COOH ethoxy CO Pyridinyl Cl COOH ethoxy CO PyridinylCl,Cl COOH ethoxy CO Pyridinyl -(1 to 4 linearly linked COOH ethoxy atomlinker)-optionally subst. aryl CO Pyridinyl -(1 to 4 linearly linkedCOOH ethoxy atom linker)-optionally subst. heteroaryl SO₂ phenyl COOHpropoxy SO₂ phenyl CF₃ COOH propoxy SO₂ phenyl CH₂CF₃ COOH propoxy SO₂phenyl Halo substituted alkyl COOH propoxy SO₂ phenyl OCH₃ COOH propoxySO₂ phenyl OCH₂CH₃ COOH propoxy SO₂ phenyl OCH₂CH₂CH₃ COOH propoxy SO₂phenyl OCH₂CH₂CH₂CH₃ COOH propoxy SO₂ phenyl OCH₂CH₂CH₂CH₂CH₃ COOHpropoxy SO₂ phenyl C5-C8 alkoxy COOH propoxy SO₂ phenyl Halo substitutedalkoxy COOH propoxy SO₂ phenyl CH₃ COOH propoxy SO₂ phenyl CH₂CH₃ COOHpropoxy SO₂ phenyl CH₂CH₂CH₃ COOH propoxy SO₂ phenyl CH₂CH₂CH₂CH₃ COOHpropoxy SO₂ phenyl C5-C8 alkyl COOH propoxy SO₂ phenyl F COOH propoxySO₂ phenyl F,F COOH propoxy SO₂ phenyl F,Cl COOH propoxy SO₂ phenyl ClCOOH propoxy SO₂ phenyl Cl,Cl COOH propoxy SO₂ phenyl -(1 to 4 linearlylinked COOH propoxy atom linker)-optionally subst. aryl SO₂ phenyl -(1to 4 linearly linked COOH propoxy atom linker)-optionally subst.heteroaryl SO₂ pyridinyl COOH propoxy SO₂ Pyridinyl CF₃ COOH propoxy SO₂Pyridinyl CH₂CF₃ COOH propoxy SO₂ Pyridinyl Halo substituted alkyl COOHpropoxy SO₂ Pyridinyl OCH₃ COOH propoxy SO₂ Pyridinyl OCH₂CH₃ COOHpropoxy SO₂ Pyridinyl OCH₂CH₂CH₃ COOH propoxy SO₂ PyridinylOCH₂CH₂CH₂CH₃ COOH propoxy SO₂ Pyridinyl OCH₂CH₂CH₂CH₂CH₃ COOH propoxySO₂ Pyridinyl C5-C8 alkoxy COOH propoxy SO₂ Pyridinyl Halo substitutedalkoxy COOH propoxy SO₂ Pyridinyl CH₃ COOH propoxy SO₂ Pyridinyl CH₂CH₃COOH propoxy SO₂ Pyridinyl CH₂CH₂CH₃ COOH propoxy SO₂ PyridinylCH₂CH₂CH₂CH₃ COOH propoxy SO₂ Pyridinyl C5-C8 alkyl COOH propoxy SO₂Pyridinyl F COOH propoxy SO₂ Pyridinyl F,F COOH propoxy SO₂ PyridinylF,Cl COOH propoxy SO₂ Pyridinyl Cl COOH propoxy SO₂ Pyridinyl Cl,Cl COOHpropoxy SO₂ Pyridinyl -(1 to 4 linearly linked COOH propoxy atomlinker)-optionally subst. aryl SO₂ Pyridinyl -(1 to 4 linearly linkedCOOH propoxy atom linker)-optionally subst. heteroaryl CO Phenyl COOHpropoxy CO Phenyl CF₃ COOH propoxy CO Phenyl CH₂CF₃ COOH propoxy COPhenyl Halo substituted alkyl COOH propoxy CO Phenyl OCH₃ COOH propoxyCO Phenyl OCH₂CH₃ COOH propoxy CO Phenyl OCH₂CH₂CH₃ COOH propoxy COPhenyl OCH₂CH₂CH₂CH₃ COOH propoxy CO Phenyl OCH₂CH₂CH₂CH₂CH₃ COOHpropoxy CO Phenyl C5-C8 alkoxy COOH propoxy CO Phenyl Halo substitutedalkoxy COOH propoxy CO Phenyl CH₃ COOH propoxy CO Phenyl CH₂CH₃ COOHpropoxy CO Phenyl CH₂CH₂CH₃ COOH propoxy CO Phenyl CH₂CH₂CH₂CH₃ COOHpropoxy CO Phenyl C5-C8 alkyl COOH propoxy CO Phenyl F COOH propoxy COPhenyl F,F COOH propoxy CO Phenyl F,Cl COOH propoxy CO Phenyl Cl COOHpropoxy CO Phenyl Cl,Cl COOH propoxy CO Phenyl -(1 to 4 linearly linkedCOOH propoxy atom linker)-optionally subst. aryl CO Phenyl -(1 to 4linearly linked COOH propoxy atom linker)-optionally subst. heteroarylCO pyridinyl COOH propoxy CO Pyridinyl CF₃ COOH propoxy CO PyridinylCH₂CF₃ COOH propoxy CO Pyridinyl Halo substituted alkyl COOH propoxy COPyridinyl OCH₃ COOH propoxy CO Pyridinyl OCH₂CH₃ COOH propoxy COPyridinyl OCH₂CH₂CH₃ COOH propoxy CO Pyridinyl OCH₂CH₂CH₂CH₃ COOHpropoxy CO Pyridinyl OCH₂CH₂CH₂CH₂CH₃ COOH propoxy CO Pyridinyl C5-C8alkoxy COOH propoxy CO Pyridinyl Halo substituted alkoxy COOH propoxy COPyridinyl CH₃ COOH propoxy CO Pyridinyl CH₂CH₃ COOH propoxy CO PyridinylCH₂CH₂CH₃ COOH propoxy CO Pyridinyl CH₂CH₂CH₂CH₃ COOH propoxy COPyridinyl C5-C8 alkyl COOH propoxy CO Pyridinyl F COOH propoxy COPyridinyl F,F COOH propoxy CO Pyridinyl F,Cl COOH propoxy CO PyridinylCl COOH propoxy CO Pyridinyl Cl,Cl COOH propoxy CO Pyridinyl -(1 to 4linearly linked COOH propoxy atom linker)-optionally subst. aryl COPyridinyl -(1 to 4 linearly linked COOH propoxy atom linker)-optionallysubst. heteroaryl SO₂ phenyl COOH —SCH₃ SO₂ phenyl CF₃ COOH —SCH₃ SO₂phenyl CH₂CF₃ COOH —SCH₃ SO₂ phenyl Halo substituted alkyl COOH —SCH₃SO₂ phenyl OCH₃ COOH —SCH₃ SO₂ phenyl OCH₂CH₃ COOH —SCH₃ SO₂ phenylOCH₂CH₂CH₃ COOH —SCH₃ SO₂ phenyl OCH₂CH₂CH₂CH₃ COOH —SCH₃ SO₂ phenylOCH₂CH₂CH₂CH₂CH₃ COOH —SCH₃ SO₂ phenyl C5-C8 alkoxy COOH —SCH₃ SO₂phenyl Halo substituted alkoxy COOH —SCH₃ SO₂ phenyl CH₃ COOH —SCH₃ SO₂phenyl CH₂CH₃ COOH —SCH₃ SO₂ phenyl CH₂CH₂CH₃ COOH —SCH₃ SO₂ phenylCH₂CH₂CH₂CH₃ COOH —SCH₃ SO₂ phenyl C5-C8 alkyl COOH —SCH₃ SO₂ phenyl FCOOH —SCH₃ SO₂ phenyl F,F COOH —SCH₃ SO₂ phenyl F,Cl COOH —SCH₃ SO₂phenyl Cl COOH —SCH₃ SO₂ phenyl Cl,Cl COOH —SCH₃ SO₂ phenyl -(1 to 4linearly linked COOH —SCH₃ atom linker)-optionally subst. aryl SO₂phenyl -(1 to 4 linearly linked COOH —SCH₃ atom linker)-optionallysubst. heteroaryl SO₂ pyridinyl COOH —SCH₃ SO₂ Pyridinyl CF₃ COOH —SCH₃SO₂ Pyridinyl CH₂CF₃ COOH —SCH₃ SO₂ Pyridinyl Halo substituted alkylCOOH —SCH₃ SO₂ Pyridinyl OCH₃ COOH —SCH₃ SO₂ Pyridinyl OCH₂CH₃ COOH—SCH₃ SO₂ Pyridinyl OCH₂CH₂CH₃ COOH —SCH₃ SO₂ Pyridinyl OCH₂CH₂CH₂CH₃COOH —SCH₃ SO₂ Pyridinyl OCH₂CH₂CH₂CH₂CH₃ COOH —SCH₃ SO₂ Pyridinyl C5-C8alkoxy COOH —SCH₃ SO₂ Pyridinyl Halo substituted alkoxy COOH —SCH₃ SO₂Pyridinyl CH₃ COOH —SCH₃ SO₂ Pyridinyl CH₂CH₃ COOH —SCH₃ SO₂ PyridinylCH₂CH₂CH₃ COOH —SCH₃ SO₂ Pyridinyl CH₂CH₂CH₂CH₃ COOH —SCH₃ SO₂ PyridinylC5-C8 alkyl COOH —SCH₃ SO₂ Pyridinyl F COOH —SCH₃ SO₂ Pyridinyl F,F COOH—SCH₃ SO₂ Pyridinyl F,Cl COOH —SCH₃ SO₂ Pyridinyl Cl COOH —SCH₃ SO₂Pyridinyl Cl,Cl COOH —SCH₃ SO₂ Pyridinyl -(1 to 4 linearly linked COOH—SCH₃ atom linker)-optionally subst. aryl SO₂ Pyridinyl -(1 to 4linearly linked COOH —SCH₃ atom linker)-optionally subst. heteroaryl COPhenyl COOH —SCH₃ CO Phenyl CF₃ COOH —SCH₃ CO Phenyl CH₂CF₃ COOH —SCH₃CO Phenyl Halo substituted alkyl COOH —SCH₃ CO Phenyl OCH₃ COOH —SCH₃ COPhenyl OCH₂CH₃ COOH —SCH₃ CO Phenyl OCH₂CH₂CH₃ COOH —SCH₃ CO PhenylOCH₂CH₂CH₂CH₃ COOH —SCH₃ CO Phenyl OCH₂CH₂CH₂CH₂CH₃ COOH —SCH₃ CO PhenylC5-C8 alkoxy COOH —SCH₃ CO Phenyl Halo substituted alkoxy COOH —SCH₃ COPhenyl CH₃ COOH —SCH₃ CO Phenyl CH₂CH₃ COOH —SCH₃ CO Phenyl CH₂CH₂CH₃COOH —SCH₃ CO Phenyl CH₂CH₂CH₂CH₃ COOH —SCH₃ CO Phenyl C5-C8 alkyl COOH—SCH₃ CO Phenyl F COOH —SCH₃ CO Phenyl F,F COOH —SCH₃ CO Phenyl F,ClCOOH —SCH₃ CO Phenyl Cl COOH —SCH₃ CO Phenyl Cl,Cl COOH —SCH₃ CO Phenyl-(1 to 4 linearly linked COOH —SCH₃ atom linker)-optionally subst. arylCO Phenyl -(1 to 4 linearly linked COOH —SCH₃ atom linker)-optionallysubst. heteroaryl CO pyridinyl COOH —SCH₃ CO Pyridinyl CF₃ COOH —SCH₃ COPyridinyl CH₂CF₃ COOH —SCH₃ CO Pyridinyl Halo substituted alkyl COOH—SCH₃ CO Pyridinyl OCH₃ COOH —SCH₃ CO Pyridinyl OCH₂CH₃ COOH —SCH₃ COPyridinyl OCH₂CH₂CH₃ COOH —SCH₃ CO Pyridinyl OCH₂CH₂CH₂CH₃ COOH —SCH₃ COPyridinyl OCH₂CH₂CH₂CH₂CH₃ COOH —SCH₃ CO Pyridinyl C5-C8 alkoxy COOH—SCH₃ CO Pyridinyl Halo substituted alkoxy COOH —SCH₃ CO Pyridinyl CH₃COOH —SCH₃ CO Pyridinyl CH₂CH₃ COOH —SCH₃ CO Pyridinyl CH₂CH₂CH₃ COOH—SCH₃ CO Pyridinyl CH₂CH₂CH₂CH₃ COOH —SCH₃ CO Pyridinyl C5-C8 alkyl COOH—SCH₃ CO Pyridinyl F COOH —SCH₃ CO Pyridinyl F,F COOH —SCH₃ CO PyridinylF,Cl COOH —SCH₃ CO Pyridinyl Cl COOH —SCH₃ CO Pyridinyl Cl,Cl COOH —SCH₃CO Pyridinyl -(1 to 4 linearly linked COOH —SCH₃ atom linker)-optionallysubst. aryl CO Pyridinyl -(1 to 4 linearly linked COOH —SCH₃ atomlinker)-optionally subst. heteroaryl SO₂ phenyl COOH —SCH₂CH₃ SO₂ phenylCF₃ COOH —SCH₂CH₃ SO₂ phenyl CH₂CF₃ COOH —SCH₂CH₃ SO₂ phenyl Halosubstituted alkyl COOH —SCH₂CH₃ SO₂ phenyl OCH₃ COOH —SCH₂CH₃ SO₂ phenylOCH₂CH₃ COOH —SCH₂CH₃ SO₂ phenyl OCH₂CH₂CH₃ COOH —SCH₂CH₃ SO₂ phenylOCH₂CH₂CH₂CH₃ COOH —SCH₂CH₃ SO₂ phenyl OCH₂CH₂CH₂CH₂CH₃ COOH —SCH₂CH₃SO₂ phenyl C5-C8 alkoxy COOH —SCH₂CH₃ SO₂ phenyl Halo substituted alkoxyCOOH —SCH₂CH₃ SO₂ phenyl CH₃ COOH —SCH₂CH₃ SO₂ phenyl CH₂CH₃ COOH—SCH₂CH₃ SO₂ phenyl CH₂CH₂CH₃ COOH —SCH₂CH₃ SO₂ phenyl CH₂CH₂CH₂CH₃ COOH—SCH₂CH₃ SO₂ phenyl C5-C8 alkyl COOH —SCH₂CH₃ SO₂ phenyl F COOH —SCH₂CH₃SO₂ phenyl F,F COOH —SCH₂CH₃ SO₂ phenyl F,Cl COOH —SCH₂CH₃ SO₂ phenyl ClCOOH —SCH₂CH₃ SO₂ phenyl Cl,Cl COOH —SCH₂CH₃ SO₂ phenyl -(1 to 4linearly linked COOH —SCH₂CH₃ atom linker)-optionally subst. aryl SO₂phenyl -(1 to 4 linearly linked COOH —SCH₂CH₃ atom linker)-optionallysubst. heteroaryl SO₂ pyridinyl COOH —SCH₂CH₃ SO₂ Pyridinyl CF₃ COOH—SCH₂CH₃ SO₂ Pyridinyl CH₂CF₃ COOH —SCH₂CH₃ SO₂ Pyridinyl Halosubstituted alkyl COOH —SCH₂CH₃ SO₂ Pyridinyl OCH₃ COOH —SCH₂CH₃ SO₂Pyridinyl OCH₂CH₃ COOH —SCH₂CH₃ SO₂ Pyridinyl OCH₂CH₂CH₃ COOH —SCH₂CH₃SO₂ Pyridinyl OCH₂CH₂CH₂CH₃ COOH —SCH₂CH₃ SO₂ Pyridinyl OCH₂CH₂CH₂CH₂CH₃COOH —SCH₂CH₃ SO₂ Pyridinyl C5-C8 alkoxy COOH —SCH₂CH₃ SO₂ PyridinylHalo substituted alkoxy COOH —SCH₂CH₃ SO₂ Pyridinyl CH₃ COOH —SCH₂CH₃SO₂ Pyridinyl CH₂CH₃ COOH —SCH₂CH₃ SO₂ Pyridinyl CH₂CH₂CH₃ COOH —SCH₂CH₃SO₂ Pyridinyl CH₂CH₂CH₂CH₃ COOH —SCH₂CH₃ SO₂ Pyridinyl C5-C8 alkyl COOH—SCH₂CH₃ SO₂ Pyridinyl F COOH —SCH₂CH₃ SO₂ Pyridinyl F,F COOH —SCH₂CH₃SO₂ Pyridinyl F,Cl COOH —SCH₂CH₃ SO₂ Pyridinyl Cl COOH —SCH₂CH₃ SO₂Pyridinyl Cl,Cl COOH —SCH₂CH₃ SO₂ Pyridinyl -(1 to 4 linearly linkedCOOH —SCH₂CH₃ atom linker)-optionally subst. aryl SO₂ Pyridinyl -(1 to 4linearly linked COOH —SCH₂CH₃ atom linker)-optionally subst. heteroarylCO Phenyl COOH —SCH₂CH₃ CO Phenyl CF₃ COOH —SCH₂CH₃ CO Phenyl CH₂CF₃COOH —SCH₂CH₃ CO Phenyl Halo substituted alkyl COOH —SCH₂CH₃ CO PhenylOCH₃ COOH —SCH₂CH₃ CO Phenyl OCH₂CH₃ COOH —SCH₂CH₃ CO Phenyl OCH₂CH₂CH₃COOH —SCH₂CH₃ CO Phenyl OCH₂CH₂CH₂CH₃ COOH —SCH₂CH₃ CO PhenylOCH₂CH₂CH₂CH₂CH₃ COOH —SCH₂CH₃ CO Phenyl C5-C8 alkoxy COOH —SCH₂CH₃ COPhenyl Halo substituted alkoxy COOH —SCH₂CH₃ CO Phenyl CH₃ COOH —SCH₂CH₃CO Phenyl CH₂CH₃ COOH —SCH₂CH₃ CO Phenyl CH₂CH₂CH₃ COOH —SCH₂CH₃ COPhenyl CH₂CH₂CH₂CH₃ COOH —SCH₂CH₃ CO Phenyl C5-C8 alkyl COOH —SCH₂CH₃ COPhenyl F COOH —SCH₂CH₃ CO Phenyl F,F COOH —SCH₂CH₃ CO Phenyl F,Cl COOH—SCH₂CH₃ CO Phenyl Cl COOH —SCH₂CH₃ CO Phenyl Cl,Cl COOH —SCH₂CH₃ COPhenyl -(1 to 4 linearly linked COOH —SCH₂CH₃ atom linker)-optionallysubst. aryl CO Phenyl -(1 to 4 linearly linked COOH —SCH₂CH₃ atomlinker)-optionally subst. heteroaryl CO pyridinyl COOH —SCH₂CH₃ COPyridinyl CF₃ COOH —SCH₂CH₃ CO Pyridinyl CH₂CF₃ COOH —SCH₂CH₃ COPyridinyl Halo substituted alkyl COOH —SCH₂CH₃ CO Pyridinyl OCH₃ COOH—SCH₂CH₃ CO Pyridinyl OCH₂CH₃ COOH —SCH₂CH₃ CO Pyridinyl OCH₂CH₂CH₃ COOH—SCH₂CH₃ CO Pyridinyl OCH₂CH₂CH₂CH₃ COOH —SCH₂CH₃ CO PyridinylOCH₂CH₂CH₂CH₂CH₃ COOH —SCH₂CH₃ CO Pyridinyl C5-C8 alkoxy COOH —SCH₂CH₃CO Pyridinyl Halo substituted alkoxy COOH —SCH₂CH₃ CO Pyridinyl CH₃ COOH—SCH₂CH₃ CO Pyridinyl CH₂CH₃ COOH —SCH₂CH₃ CO Pyridinyl CH₂CH₂CH₃ COOH—SCH₂CH₃ CO Pyridinyl CH₂CH₂CH₂CH₃ COOH —SCH₂CH₃ CO Pyridinyl C5-C8alkyl COOH —SCH₂CH₃ CO Pyridinyl F COOH —SCH₂CH₃ CO Pyridinyl F,F COOH—SCH₂CH₃ CO Pyridinyl F,Cl COOH —SCH₂CH₃ CO Pyridinyl Cl COOH —SCH₂CH₃CO Pyridinyl Cl,Cl COOH —SCH₂CH₃ CO Pyridinyl -(1 to 4 linearly linkedCOOH —SCH₂CH₃ atom linker)-optionally subst. aryl CO Pyridinyl -(1 to 4linearly linked COOH —SCH₂CH₃ atom linker)-optionally subst. heteroarylSO₂ phenyl tetrazole methoxy SO₂ phenyl CF₃ Tetrazole methoxy SO₂ phenylCH₂CF₃ Tetrazole methoxy SO₂ phenyl Halo substituted alkyl Tetrazolemethoxy SO₂ phenyl OCH₃ Tetrazole methoxy SO₂ phenyl OCH₂CH₃ tetrazolemethoxy SO₂ phenyl OCH₂CH₂CH₃ tetrazole methoxy SO₂ phenyl OCH₂CH₂CH₂CH₃Tetrazole methoxy SO₂ phenyl OCH₂CH₂CH₂CH₂CH₃ Tetrazole methoxy SO₂phenyl C5-C8 alkoxy Tetrazole methoxy SO₂ phenyl Halo substituted alkoxyTetrazole methoxy SO₂ phenyl CH₃ tetrazole methoxy SO₂ phenyl CH₂CH₃tetrazole methoxy SO₂ phenyl CH₂CH₂CH₃ Tetrazole methoxy SO₂ phenylCH₂CH₂CH₂CH₃ Tetrazole methoxy SO₂ phenyl C5-C8 alkyl Tetrazole methoxySO₂ phenyl F Tetrazole methoxy SO₂ phenyl F,F tetrazole methoxy SO₂phenyl F,Cl tetrazole methoxy SO₂ phenyl Cl Tetrazole methoxy SO₂ phenylCl,Cl Tetrazole methoxy SO₂ phenyl -(1 to 4 linearly linked Tetrazolemethoxy atom linker)-optionally subst. aryl SO₂ phenyl -(1 to 4 linearlylinked Tetrazole methoxy atom linker)-optionally subst. heteroaryl SO₂pyridinyl tetrazole methoxy SO₂ Pyridinyl CF₃ tetrazole methoxy SO₂Pyridinyl CH₂CF₃ Tetrazole methoxy SO₂ Pyridinyl Halo substituted alkylTetrazole methoxy SO₂ Pyridinyl OCH₃ Tetrazole methoxy SO₂ PyridinylOCH₂CH₃ Tetrazole methoxy SO₂ Pyridinyl OCH₂CH₂CH₃ tetrazole methoxy SO₂Pyridinyl OCH₂CH₂CH₂CH₃ tetrazole methoxy SO₂ Pyridinyl OCH₂CH₂CH₂CH₂CH₃Tetrazole methoxy SO₂ Pyridinyl C5-C8 alkoxy Tetrazole methoxy SO₂Pyridinyl Halo substituted alkoxy Tetrazole methoxy SO₂ Pyridinyl CH₃Tetrazole methoxy SO₂ Pyridinyl CH₂CH₃ tetrazole methoxy SO₂ PyridinylCH₂CH₂CH₃ tetrazole methoxy SO₂ Pyridinyl CH₂CH₂CH₂CH₃ Tetrazole methoxySO₂ Pyridinyl C5-C8 alkyl Tetrazole methoxy SO₂ Pyridinyl F Tetrazolemethoxy SO₂ Pyridinyl F,F Tetrazole methoxy SO₂ Pyridinyl F,Cl tetrazolemethoxy SO₂ Pyridinyl Cl tetrazole methoxy SO₂ Pyridinyl Cl,Cl Tetrazolemethoxy SO₂ Pyridinyl -(1 to 4 linearly linked Tetrazole methoxy atomlinker)-optionally subst. aryl SO₂ Pyridinyl -(1 to 4 linearly linkedTetrazole methoxy atom linker)-optionally subst. heteroaryl CO PhenylTetrazole methoxy CO Phenyl CF₃ tetrazole methoxy CO Phenyl CH₂CF₃tetrazole methoxy CO Phenyl Halo substituted alkyl Tetrazole methoxy COPhenyl OCH₃ Tetrazole methoxy CO Phenyl OCH₂CH₃ Tetrazole methoxy COPhenyl OCH₂CH₂CH₃ Tetrazole methoxy CO Phenyl OCH₂CH₂CH₂CH₃ tetrazolemethoxy CO Phenyl OCH₂CH₂CH₂CH₂CH₃ tetrazole methoxy CO Phenyl C5-C8alkoxy Tetrazole methoxy CO Phenyl Halo substituted alkoxy Tetrazolemethoxy CO Phenyl CH₃ Tetrazole methoxy CO Phenyl CH₂CH₃ Tetrazolemethoxy CO Phenyl CH₂CH₂CH₃ tetrazole methoxy CO Phenyl CH₂CH₂CH₂CH₃tetrazole methoxy CO Phenyl C5-C8 alkyl Tetrazole methoxy CO Phenyl FTetrazole methoxy CO Phenyl F,F Tetrazole methoxy CO Phenyl F,ClTetrazole methoxy CO Phenyl Cl tetrazole methoxy CO Phenyl Cl,Cltetrazole methoxy CO Phenyl -(1 to 4 linearly linked Tetrazole methoxyatom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearly linkedTetrazole methoxy atom linker)-optionally subst. heteroaryl CO pyridinylTetrazole methoxy CO Pyridinyl CF₃ Tetrazole methoxy CO Pyridinyl CH₂CF₃tetrazole methoxy CO Pyridinyl Halo substituted alkyl tetrazole methoxyCO Pyridinyl OCH₃ Tetrazole methoxy CO Pyridinyl OCH₂CH₃ Tetrazolemethoxy CO Pyridinyl OCH₂CH₂CH₃ Tetrazole methoxy CO PyridinylOCH₂CH₂CH₂CH₃ Tetrazole methoxy CO Pyridinyl OCH₂CH₂CH₂CH₂CH₃ tetrazolemethoxy CO Pyridinyl C5-C8 alkoxy tetrazole methoxy CO Pyridinyl Halosubstituted alkoxy Tetrazole methoxy CO Pyridinyl CH₃ Tetrazole methoxyCO Pyridinyl CH₂CH₃ Tetrazole methoxy CO Pyridinyl CH₂CH₂CH₃ Tetrazolemethoxy CO Pyridinyl CH₂CH₂CH₂CH₃ tetrazole methoxy CO Pyridinyl C5-C8alkyl tetrazole methoxy CO Pyridinyl F Tetrazole methoxy CO PyridinylF,F Tetrazole methoxy CO Pyridinyl F,Cl Tetrazole methoxy CO PyridinylCl Tetrazole methoxy CO Pyridinyl Cl,Cl tetrazole methoxy CO Pyridinyl-(1 to 4 linearly linked tetrazole methoxy atom linker)-optionallysubst. aryl CO Pyridinyl -(1 to 4 linearly linked Tetrazole methoxy atomlinker)-optionally subst. heteroaryl SO₂ phenyl Tetrazole ethoxy SO₂phenyl CF₃ Tetrazole ethoxy SO₂ phenyl CH₂CF₃ Tetrazole ethoxy SO₂phenyl Halo substituted alkyl tetrazole ethoxy SO₂ phenyl OCH₃ tetrazoleethoxy SO₂ phenyl OCH₂CH₃ Tetrazole ethoxy SO₂ phenyl OCH₂CH₂CH₃Tetrazole ethoxy SO₂ phenyl OCH₂CH₂CH₂CH₃ Tetrazole ethoxy SO₂ phenylOCH₂CH₂CH₂CH₂CH₃ Tetrazole ethoxy SO₂ phenyl C5-C8 alkoxy tetrazoleethoxy SO₂ phenyl Halo substituted alkoxy tetrazole ethoxy SO₂ phenylCH₃ Tetrazole ethoxy SO₂ phenyl CH₂CH₃ Tetrazole ethoxy SO₂ phenylCH₂CH₂CH₃ Tetrazole ethoxy SO₂ phenyl CH₂CH₂CH₂CH₃ Tetrazole ethoxy SO₂phenyl C5-C8 alkyl tetrazole ethoxy SO₂ phenyl F tetrazole ethoxy SO₂phenyl F,F Tetrazole ethoxy SO₂ phenyl F,Cl Tetrazole ethoxy SO₂ phenylCl Tetrazole ethoxy SO₂ phenyl Cl,Cl Tetrazole ethoxy SO₂ phenyl -(1 to4 linearly linked tetrazole ethoxy atom linker)-optionally subst. arylSO₂ phenyl -(1 to 4 linearly linked tetrazole ethoxy atomlinker)-optionally subst. heteroaryl SO₂ pyridinyl Tetrazole ethoxy SO₂Pyridinyl CF₃ Tetrazole ethoxy SO₂ Pyridinyl CH₂CF₃ Tetrazole ethoxy SO₂Pyridinyl Halo substituted alkyl Tetrazole ethoxy SO₂ Pyridinyl OCH₃tetrazole ethoxy SO₂ Pyridinyl OCH₂CH₃ tetrazole ethoxy SO₂ PyridinylOCH₂CH₂CH₃ Tetrazole ethoxy SO₂ Pyridinyl OCH₂CH₂CH₂CH₃ Tetrazole ethoxySO₂ Pyridinyl OCH₂CH₂CH₂CH₂CH₃ Tetrazole ethoxy SO₂ Pyridinyl C5-C8alkoxy Tetrazole ethoxy SO₂ Pyridinyl Halo substituted alkoxy tetrazoleethoxy SO₂ Pyridinyl CH₃ tetrazole ethoxy SO₂ Pyridinyl CH₂CH₃ Tetrazoleethoxy SO₂ Pyridinyl CH₂CH₂CH₃ Tetrazole ethoxy SO₂ PyridinylCH₂CH₂CH₂CH₃ Tetrazole ethoxy SO₂ Pyridinyl C5-C8 alkyl Tetrazole ethoxySO₂ Pyridinyl F tetrazole ethoxy SO₂ Pyridinyl F,F tetrazole ethoxy SO₂Pyridinyl F,Cl Tetrazole ethoxy SO₂ Pyridinyl Cl Tetrazole ethoxy SO₂Pyridinyl Cl,Cl Tetrazole ethoxy SO₂ Pyridinyl -(1 to 4 linearly linkedTetrazole ethoxy atom linker)-optionally subst. aryl SO₂ Pyridinyl -(1to 4 linearly linked tetrazole ethoxy atom linker)-optionally subst.heteroaryl CO Phenyl tetrazole ethoxy CO Phenyl CF₃ Tetrazole ethoxy COPhenyl CH₂CF₃ Tetrazole ethoxy CO Phenyl Halo substituted alkylTetrazole ethoxy CO Phenyl OCH₃ Tetrazole ethoxy CO Phenyl OCH₂CH₃tetrazole ethoxy CO Phenyl OCH₂CH₂CH₃ tetrazole ethoxy CO PhenylOCH₂CH₂CH₂CH₃ Tetrazole ethoxy CO Phenyl OCH₂CH₂CH₂CH₂CH₃ Tetrazoleethoxy CO Phenyl C5-C8 alkoxy Tetrazole ethoxy CO Phenyl Halosubstituted alkoxy Tetrazole ethoxy CO Phenyl CH₃ tetrazole ethoxy COPhenyl CH₂CH₃ tetrazole ethoxy CO Phenyl CH₂CH₂CH₃ Tetrazole ethoxy COPhenyl CH₂CH₂CH₂CH₃ Tetrazole ethoxy CO Phenyl C5-C8 alkyl Tetrazoleethoxy CO Phenyl F Tetrazole ethoxy CO Phenyl F,F tetrazole ethoxy COPhenyl F,Cl tetrazole ethoxy CO Phenyl Cl Tetrazole ethoxy CO PhenylCl,Cl Tetrazole ethoxy CO Phenyl -(1 to 4 linearly linked Tetrazoleethoxy atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearlylinked Tetrazole ethoxy atom linker)-optionally subst. heteroaryl COpyridinyl tetrazole ethoxy CO Pyridinyl CF₃ tetrazole ethoxy COPyridinyl CH₂CF₃ Tetrazole ethoxy CO Pyridinyl Halo substituted alkylTetrazole ethoxy CO Pyridinyl OCH₃ Tetrazole ethoxy CO Pyridinyl OCH₂CH₃Tetrazole ethoxy CO Pyridinyl OCH₂CH₂CH₃ tetrazole ethoxy CO PyridinylOCH₂CH₂CH₂CH₃ tetrazole ethoxy CO Pyridinyl OCH₂CH₂CH₂CH₂CH₃ Tetrazoleethoxy CO Pyridinyl C5-C8 alkoxy Tetrazole ethoxy CO Pyridinyl Halosubstituted alkoxy Tetrazole ethoxy CO Pyridinyl CH₃ Tetrazole ethoxy COPyridinyl CH₂CH₃ tetrazole ethoxy CO Pyridinyl CH₂CH₂CH₃ tetrazoleethoxy CO Pyridinyl CH₂CH₂CH₂CH₃ Tetrazole ethoxy CO Pyridinyl C5-C8alkyl Tetrazole ethoxy CO Pyridinyl F Tetrazole ethoxy CO Pyridinyl F,FTetrazole ethoxy CO Pyridinyl F,Cl tetrazole ethoxy CO Pyridinyl Cltetrazole ethoxy CO Pyridinyl Cl,Cl Tetrazole ethoxy CO Pyridinyl -(1 to4 linearly linked Tetrazole ethoxy atom linker)-optionally subst. arylCO Pyridinyl -(1 to 4 linearly linked Tetrazole ethoxy atomlinker)-optionally subst. heteroaryl SO₂ phenyl tetrazole propoxy SO₂phenyl CF₃ Tetrazole propoxy SO₂ phenyl CH₂CF₃ Tetrazole propoxy SO₂phenyl Halo substituted alkyl Tetrazole propoxy SO₂ phenyl OCH₃Tetrazole propoxy SO₂ phenyl OCH₂CH₃ tetrazole propoxy SO₂ phenylOCH₂CH₂CH₃ tetrazole propoxy SO₂ phenyl OCH₂CH₂CH₂CH₃ Tetrazole propoxySO₂ phenyl OCH₂CH₂CH₂CH₂CH₃ Tetrazole propoxy SO₂ phenyl C5-C8 alkoxyTetrazole propoxy SO₂ phenyl Halo substituted alkoxy Tetrazole propoxySO₂ phenyl CH₃ tetrazole propoxy SO₂ phenyl CH₂CH₃ tetrazole propoxy SO₂phenyl CH₂CH₂CH₃ Tetrazole propoxy SO₂ phenyl CH₂CH₂CH₂CH₃ Tetrazolepropoxy SO₂ phenyl C5-C8 alkyl Tetrazole propoxy SO₂ phenyl F Tetrazolepropoxy SO₂ phenyl F,F tetrazole propoxy SO₂ phenyl F,Cl tetrazolepropoxy SO₂ phenyl Cl Tetrazole propoxy SO₂ phenyl Cl,Cl Tetrazolepropoxy SO₂ phenyl -(1 to 4 linearly linked Tetrazole propoxy atomlinker)-optionally subst. aryl SO₂ phenyl -(1 to 4 linearly linkedTetrazole propoxy atom linker)-optionally subst. heteroaryl SO₂pyridinyl tetrazole propoxy SO₂ Pyridinyl CF₃ tetrazole propoxy SO₂Pyridinyl CH₂CF₃ Tetrazole propoxy SO₂ Pyridinyl Halo substituted alkylTetrazole propoxy SO₂ Pyridinyl OCH₃ Tetrazole propoxy SO₂ PyridinylOCH₂CH₃ Tetrazole propoxy SO₂ Pyridinyl OCH₂CH₂CH₃ tetrazole propoxy SO₂Pyridinyl OCH₂CH₂CH₂CH₃ tetrazole propoxy SO₂ Pyridinyl OCH₂CH₂CH₂CH₂CH₃Tetrazole propoxy SO₂ Pyridinyl C5-C8 alkoxy Tetrazole propoxy SO₂Pyridinyl Halo substituted alkoxy Tetrazole propoxy SO₂ Pyridinyl CH₃Tetrazole propoxy SO₂ Pyridinyl CH₂CH₃ tetrazole propoxy SO₂ PyridinylCH₂CH₂CH₃ tetrazole propoxy SO₂ Pyridinyl CH₂CH₂CH₂CH₃ Tetrazole propoxySO₂ Pyridinyl C5-C8 alkyl Tetrazole propoxy SO₂ Pyridinyl F Tetrazolepropoxy SO₂ Pyridinyl F,F Tetrazole propoxy SO₂ Pyridinyl F,Cl tetrazolepropoxy SO₂ Pyridinyl Cl tetrazole propoxy SO₂ Pyridinyl Cl,Cl Tetrazolepropoxy SO₂ Pyridinyl -(1 to 4 linearly linked Tetrazole propoxy atomlinker)-optionally subst. aryl SO₂ Pyridinyl -(1 to 4 linearly linkedTetrazole propoxy atom linker)-optionally subst. heteroaryl CO PhenylTetrazole propoxy CO Phenyl CF₃ tetrazole propoxy CO Phenyl CH₂CF₃tetrazole propoxy CO Phenyl Halo substituted alkyl Tetrazole propoxy COPhenyl OCH₃ Tetrazole propoxy CO Phenyl OCH₂CH₃ Tetrazole propoxy COPhenyl OCH₂CH₂CH₃ Tetrazole propoxy CO Phenyl OCH₂CH₂CH₂CH₃ tetrazolepropoxy CO Phenyl OCH₂CH₂CH₂CH₂CH₃ tetrazole propoxy CO Phenyl C5-C8alkoxy Tetrazole propoxy CO Phenyl Halo substituted alkoxy Tetrazolepropoxy CO Phenyl CH₃ Tetrazole propoxy CO Phenyl CH₂CH₃ Tetrazolepropoxy CO Phenyl CH₂CH₂CH₃ tetrazole propoxy CO Phenyl CH₂CH₂CH₂CH₃tetrazole propoxy CO Phenyl C5-C8 alkyl Tetrazole propoxy CO Phenyl FTetrazole propoxy CO Phenyl F,F Tetrazole propoxy CO Phenyl F,ClTetrazole propoxy CO Phenyl Cl tetrazole propoxy CO Phenyl Cl,Cltetrazole propoxy CO Phenyl -(1 to 4 linearly linked Tetrazole propoxyatom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearly linkedTetrazole propoxy atom linker)-optionally subst. heteroaryl CO pyridinylTetrazole propoxy CO Pyridinyl CF₃ Tetrazole propoxy CO Pyridinyl CH₂CF₃tetrazole propoxy CO Pyridinyl Halo substituted alkyl tetrazole propoxyCO Pyridinyl OCH₃ Tetrazole propoxy CO Pyridinyl OCH₂CH₃ Tetrazolepropoxy CO Pyridinyl OCH₂CH₂CH₃ Tetrazole propoxy CO PyridinylOCH₂CH₂CH₂CH₃ Tetrazole propoxy CO Pyridinyl OCH₂CH₂CH₂CH₂CH₃ tetrazolepropoxy CO Pyridinyl C5-C8 alkoxy tetrazole propoxy CO Pyridinyl Halosubstituted alkoxy Tetrazole propoxy CO Pyridinyl CH₃ Tetrazole propoxyCO Pyridinyl CH₂CH₃ Tetrazole propoxy CO Pyridinyl CH₂CH₂CH₃ Tetrazolepropoxy CO Pyridinyl CH₂CH₂CH₂CH₃ tetrazole propoxy CO Pyridinyl C5-C8alkyl tetrazole propoxy CO Pyridinyl F Tetrazole propoxy CO PyridinylF,F Tetrazole propoxy CO Pyridinyl F,Cl Tetrazole propoxy CO PyridinylCl Tetrazole propoxy CO Pyridinyl Cl,Cl tetrazole propoxy CO Pyridinyl-(1 to 4 linearly linked tetrazole propoxy atom linker)-optionallysubst. aryl CO Pyridinyl -(1 to 4 linearly linked Tetrazole propoxy atomlinker)-optionally subst. heteroaryl SO₂ phenyl Tetrazole —SCH₃ SO₂phenyl CF₃ Tetrazole —SCH₃ SO₂ phenyl CH₂CF₃ Tetrazole —SCH₃ SO₂ phenylHalo substituted alkyl tetrazole —SCH₃ SO₂ phenyl OCH₃ tetrazole —SCH₃SO₂ phenyl OCH₂CH₃ Tetrazole —SCH₃ SO₂ phenyl OCH₂CH₂CH₃ Tetrazole —SCH₃SO₂ phenyl OCH₂CH₂CH₂CH₃ Tetrazole —SCH₃ SO₂ phenyl OCH₂CH₂CH₂CH₂CH₃Tetrazole —SCH₃ SO₂ phenyl C5-C8 alkoxy tetrazole —SCH₃ SO₂ phenyl Halosubstituted alkoxy tetrazole —SCH₃ SO₂ phenyl CH₃ Tetrazole —SCH₃ SO₂phenyl CH₂CH₃ Tetrazole —SCH₃ SO₂ phenyl CH₂CH₂CH₃ Tetrazole —SCH₃ SO₂phenyl CH₂CH₂CH₂CH₃ Tetrazole —SCH₃ SO₂ phenyl C5-C8 alkyl tetrazole—SCH₃ SO₂ phenyl F tetrazole —SCH₃ SO₂ phenyl F,F Tetrazole —SCH₃ SO₂phenyl F,Cl Tetrazole —SCH₃ SO₂ phenyl Cl Tetrazole —SCH₃ SO₂ phenylCl,Cl Tetrazole —SCH₃ SO₂ phenyl -(1 to 4 linearly linked tetrazole—SCH₃ atom linker)-optionally subst. aryl SO₂ phenyl -(1 to 4 linearlylinked tetrazole —SCH₃ atom linker)-optionally subst. heteroaryl SO₂pyridinyl Tetrazole —SCH₃ SO₂ Pyridinyl CF₃ Tetrazole —SCH₃ SO₂Pyridinyl CH₂CF₃ Tetrazole —SCH₃ SO₂ Pyridinyl Halo substituted alkylTetrazole —SCH₃ SO₂ Pyridinyl OCH₃ tetrazole —SCH₃ SO₂ Pyridinyl OCH₂CH₃tetrazole —SCH₃ SO₂ Pyridinyl OCH₂CH₂CH₃ Tetrazole —SCH₃ SO₂ PyridinylOCH₂CH₂CH₂CH₃ Tetrazole —SCH₃ SO₂ Pyridinyl OCH₂CH₂CH₂CH₂CH₃ Tetrazole—SCH₃ SO₂ Pyridinyl C5-C8 alkoxy Tetrazole —SCH₃ SO₂ Pyridinyl Halosubstituted alkoxy tetrazole —SCH₃ SO₂ Pyridinyl CH₃ tetrazole —SCH₃ SO₂Pyridinyl CH₂CH₃ Tetrazole —SCH₃ SO₂ Pyridinyl CH₂CH₂CH₃ Tetrazole —SCH₃SO₂ Pyridinyl CH₂CH₂CH₂CH₃ Tetrazole —SCH₃ SO₂ Pyridinyl C5-C8 alkylTetrazole —SCH₃ SO₂ Pyridinyl F tetrazole —SCH₃ SO₂ Pyridinyl F,Ftetrazole —SCH₃ SO₂ Pyridinyl F,Cl Tetrazole —SCH₃ SO₂ Pyridinyl ClTetrazole —SCH₃ SO₂ Pyridinyl Cl,Cl Tetrazole —SCH₃ SO₂ Pyridinyl -(1 to4 linearly linked Tetrazole —SCH₃ atom linker)-optionally subst. arylSO₂ Pyridinyl -(1 to 4 linearly linked tetrazole —SCH₃ atomlinker)-optionally subst. heteroaryl CO Phenyl tetrazole —SCH₃ CO PhenylCF₃ Tetrazole —SCH₃ CO Phenyl CH₂CF₃ Tetrazole —SCH₃ CO Phenyl Halosubstituted alkyl Tetrazole —SCH₃ CO Phenyl OCH₃ Tetrazole —SCH₃ COPhenyl OCH₂CH₃ tetrazole —SCH₃ CO Phenyl OCH₂CH₂CH₃ tetrazole —SCH₃ COPhenyl OCH₂CH₂CH₂CH₃ Tetrazole —SCH₃ CO Phenyl OCH₂CH₂CH₂CH₂CH₃Tetrazole —SCH₃ CO Phenyl C5-C8 alkoxy Tetrazole —SCH₃ CO Phenyl Halosubstituted alkoxy Tetrazole —SCH₃ CO Phenyl CH₃ tetrazole —SCH₃ COPhenyl CH₂CH₃ tetrazole —SCH₃ CO Phenyl CH₂CH₂CH₃ Tetrazole —SCH₃ COPhenyl CH₂CH₂CH₂CH₃ Tetrazole —SCH₃ CO Phenyl C5-C8 alkyl Tetrazole—SCH₃ CO Phenyl F Tetrazole —SCH₃ CO Phenyl F,F tetrazole —SCH₃ COPhenyl F,Cl tetrazole —SCH₃ CO Phenyl Cl Tetrazole —SCH₃ CO Phenyl Cl,ClTetrazole —SCH₃ CO Phenyl -(1 to 4 linearly linked Tetrazole —SCH₃ atomlinker)-optionally subst. aryl CO Phenyl -(1 to 4 linearly linkedTetrazole —SCH₃ atom linker)-optionally subst. heteroaryl CO pyridinyltetrazole —SCH₃ CO Pyridinyl CF₃ tetrazole —SCH₃ CO Pyridinyl CH₂CF₃Tetrazole —SCH₃ CO Pyridinyl Halo substituted alkyl Tetrazole —SCH₃ COPyridinyl OCH₃ Tetrazole —SCH₃ CO Pyridinyl OCH₂CH₃ Tetrazole —SCH₃ COPyridinyl OCH₂CH₂CH₃ tetrazole —SCH₃ CO Pyridinyl OCH₂CH₂CH₂CH₃tetrazole —SCH₃ CO Pyridinyl OCH₂CH₂CH₂CH₂CH₃ Tetrazole —SCH₃ COPyridinyl C5-C8 alkoxy Tetrazole —SCH₃ CO Pyridinyl Halo substitutedalkoxy Tetrazole —SCH₃ CO Pyridinyl CH₃ Tetrazole —SCH₃ CO PyridinylCH₂CH₃ tetrazole —SCH₃ CO Pyridinyl CH₂CH₂CH₃ tetrazole —SCH₃ COPyridinyl CH₂CH₂CH₂CH₃ Tetrazole —SCH₃ CO Pyridinyl C5-C8 alkylTetrazole —SCH₃ CO Pyridinyl F Tetrazole —SCH₃ CO Pyridinyl F,FTetrazole —SCH₃ CO Pyridinyl F,Cl tetrazole —SCH₃ CO Pyridinyl Cltetrazole —SCH₃ CO Pyridinyl Cl,Cl Tetrazole —SCH₃ CO Pyridinyl -(1 to 4linearly linked Tetrazole —SCH₃ atom linker)-optionally subst. aryl COPyridinyl -(1 to 4 linearly linked Tetrazole —SCH₃ atomlinker)-optionally subst. heteroaryl SO₂ phenyl Tetrazole —SCH₂CH₃ SO₂phenyl CF₃ tetrazole —SCH₂CH₃ SO₂ phenyl CH₂CF₃ tetrazole —SCH₂CH₃ SO₂phenyl Halo substituted alkyl Tetrazole —SCH₂CH₃ SO₂ phenyl OCH₃Tetrazole —SCH₂CH₃ SO₂ phenyl OCH₂CH₃ Tetrazole —SCH₂CH₃ SO₂ phenylOCH₂CH₂CH₃ Tetrazole —SCH₂CH₃ SO₂ phenyl OCH₂CH₂CH₂CH₃ tetrazole—SCH₂CH₃ SO₂ phenyl OCH₂CH₂CH₂CH₂CH₃ tetrazole —SCH₂CH₃ SO₂ phenyl C5-C8alkoxy Tetrazole —SCH₂CH₃ SO₂ phenyl Halo substituted alkoxy Tetrazole—SCH₂CH₃ SO₂ phenyl CH₃ Tetrazole —SCH₂CH₃ SO₂ phenyl CH₂CH₃ Tetrazole—SCH₂CH₃ SO₂ phenyl CH₂CH₂CH₃ tetrazole —SCH₂CH₃ SO₂ phenyl CH₂CH₂CH₂CH₃tetrazole —SCH₂CH₃ SO₂ phenyl C5-C8 alkyl Tetrazole —SCH₂CH₃ SO₂ phenylF Tetrazole —SCH₂CH₃ SO₂ phenyl F,F Tetrazole —SCH₂CH₃ SO₂ phenyl F,ClTetrazole —SCH₂CH₃ SO₂ phenyl Cl tetrazole —SCH₂CH₃ SO₂ phenyl Cl,Cltetrazole —SCH₂CH₃ SO₂ phenyl -(1 to 4 linearly linked Tetrazole—SCH₂CH₃ atom linker)-optionally subst. aryl SO₂ phenyl -(1 to 4linearly linked Tetrazole —SCH₂CH₃ atom linker)-optionally subst.heteroaryl SO₂ pyridinyl Tetrazole —SCH₂CH₃ SO₂ Pyridinyl CF₃ Tetrazole—SCH₂CH₃ SO₂ Pyridinyl CH₂CF₃ tetrazole —SCH₂CH₃ SO₂ Pyridinyl Halosubstituted alkyl tetrazole —SCH₂CH₃ SO₂ Pyridinyl OCH₃ Tetrazole—SCH₂CH₃ SO₂ Pyridinyl OCH₂CH₃ Tetrazole —SCH₂CH₃ SO₂ PyridinylOCH₂CH₂CH₃ Tetrazole —SCH₂CH₃ SO₂ Pyridinyl OCH₂CH₂CH₂CH₃ Tetrazole—SCH₂CH₃ SO₂ Pyridinyl OCH₂CH₂CH₂CH₂CH₃ tetrazole —SCH₂CH₃ SO₂ PyridinylC5-C8 alkoxy tetrazole —SCH₂CH₃ SO₂ Pyridinyl Halo substituted alkoxyTetrazole —SCH₂CH₃ SO₂ Pyridinyl CH₃ Tetrazole —SCH₂CH₃ SO₂ PyridinylCH₂CH₃ Tetrazole —SCH₂CH₃ SO₂ Pyridinyl CH₂CH₂CH₃ Tetrazole —SCH₂CH₃ SO₂Pyridinyl CH₂CH₂CH₂CH₃ tetrazole —SCH₂CH₃ SO₂ Pyridinyl C5-C8 alkyltetrazole —SCH₂CH₃ SO₂ Pyridinyl F Tetrazole —SCH₂CH₃ SO₂ Pyridinyl F,FTetrazole —SCH₂CH₃ SO₂ Pyridinyl F,Cl Tetrazole —SCH₂CH₃ SO₂ PyridinylCl Tetrazole —SCH₂CH₃ SO₂ Pyridinyl Cl,Cl tetrazole —SCH₂CH₃ SO₂Pyridinyl -(1 to 4 linearly linked tetrazole —SCH₂CH₃ atomlinker)-optionally subst. aryl SO₂ Pyridinyl -(1 to 4 linearly linkedTetrazole —SCH₂CH₃ atom linker)-optionally subst. heteroaryl CO PhenylTetrazole —SCH₂CH₃ CO Phenyl CF₃ Tetrazole —SCH₂CH₃ CO Phenyl CH₂CF₃Tetrazole —SCH₂CH₃ CO Phenyl Halo substituted alkyl tetrazole —SCH₂CH₃CO Phenyl OCH₃ tetrazole —SCH₂CH₃ CO Phenyl OCH₂CH₃ Tetrazole —SCH₂CH₃CO Phenyl OCH₂CH₂CH₃ Tetrazole —SCH₂CH₃ CO Phenyl OCH₂CH₂CH₂CH₃Tetrazole —SCH₂CH₃ CO Phenyl OCH₂CH₂CH₂CH₂CH₃ Tetrazole —SCH₂CH₃ COPhenyl C5-C8 alkoxy tetrazole —SCH₂CH₃ CO Phenyl Halo substituted alkoxytetrazole —SCH₂CH₃ CO Phenyl CH₃ Tetrazole —SCH₂CH₃ CO Phenyl CH₂CH₃Tetrazole —SCH₂CH₃ CO Phenyl CH₂CH₂CH₃ Tetrazole —SCH₂CH₃ CO PhenylCH₂CH₂CH₂CH₃ Tetrazole —SCH₂CH₃ CO Phenyl C5-C8 alkyl tetrazole —SCH₂CH₃CO Phenyl F tetrazole —SCH₂CH₃ CO Phenyl F,F Tetrazole —SCH₂CH₃ COPhenyl F,Cl Tetrazole —SCH₂CH₃ CO Phenyl Cl Tetrazole —SCH₂CH₃ CO PhenylCl,Cl Tetrazole —SCH₂CH₃ CO Phenyl -(1 to 4 linearly linked tetrazole—SCH₂CH₃ atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearlylinked tetrazole —SCH₂CH₃ atom linker)-optionally subst. heteroaryl COpyridinyl Tetrazole —SCH₂CH₃ CO Pyridinyl CF₃ Tetrazole —SCH₂CH₃ COPyridinyl CH₂CF₃ Tetrazole —SCH₂CH₃ CO Pyridinyl Halo substituted alkylTetrazole —SCH₂CH₃ CO Pyridinyl OCH₃ tetrazole —SCH₂CH₃ CO PyridinylOCH₂CH₃ tetrazole —SCH₂CH₃ CO Pyridinyl OCH₂CH₂CH₃ Tetrazole —SCH₂CH₃ COPyridinyl OCH₂CH₂CH₂CH₃ Tetrazole —SCH₂CH₃ CO Pyridinyl OCH₂CH₂CH₂CH₂CH₃Tetrazole —SCH₂CH₃ CO Pyridinyl C5-C8 alkoxy Tetrazole —SCH₂CH₃ COPyridinyl Halo substituted alkoxy tetrazole —SCH₂CH₃ CO Pyridinyl CH₃tetrazole —SCH₂CH₃ CO Pyridinyl CH₂CH₃ Tetrazole —SCH₂CH₃ CO PyridinylCH₂CH₂CH₃ Tetrazole —SCH₂CH₃ CO Pyridinyl CH₂CH₂CH₂CH₃ Tetrazole—SCH₂CH₃ CO Pyridinyl C5-C8 alkyl Tetrazole —SCH₂CH₃ CO Pyridinyl Ftetrazole —SCH₂CH₃ CO Pyridinyl F,F tetrazole —SCH₂CH₃ CO Pyridinyl F,ClTetrazole —SCH₂CH₃ CO Pyridinyl Cl Tetrazole —SCH₂CH₃ CO Pyridinyl Cl,ClTetrazole —SCH₂CH₃ CO Pyridinyl -(1 to 4 linearly linked Tetrazole—SCH₂CH₃ atom linker)-optionally subst. aryl CO Pyridinyl -(1 to 4linearly linked tetrazole —SCH₂CH₃ atom linker)-optionally subst.heteroaryl SO₂ phenyl 3-hydroxy isoxazole methoxy SO₂ phenyl CF₃3-hydroxy isoxazole methoxy SO₂ phenyl CH₂CF₃ 3-hydroxy isoxazolemethoxy SO₂ phenyl Halo substituted alkyl 3-hydroxy isoxazole methoxySO₂ phenyl OCH₃ 3-hydroxy isoxazole methoxy SO₂ phenyl OCH₂CH₃ 3-hydroxyisoxazole methoxy SO₂ phenyl OCH₂CH₂CH₃ 3-hydroxy isoxazole methoxy SO₂phenyl OCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole methoxy SO₂ phenylOCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole methoxy SO₂ phenyl C5-C8 alkoxy3-hydroxy isoxazole methoxy SO₂ phenyl Halo substituted alkoxy 3-hydroxyisoxazole methoxy SO₂ phenyl CH₃ 3-hydroxy isoxazole methoxy SO₂ phenylCH₂CH₃ 3-hydroxy isoxazole methoxy SO₂ phenyl CH₂CH₂CH₃ 3-hydroxyisoxazole methoxy SO₂ phenyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole methoxySO₂ phenyl C5-C8 alkyl 3-hydroxy isoxazole methoxy SO₂ phenyl F3-hydroxy isoxazole methoxy SO₂ phenyl F,F 3-hydroxy isoxazole methoxySO₂ phenyl F,Cl 3-hydroxy isoxazole methoxy SO₂ phenyl Cl 3-hydroxyisoxazole methoxy SO₂ phenyl Cl,Cl 3-hydroxy isoxazole methoxy SO₂phenyl -(1 to 4 linearly linked 3-hydroxy isoxazole methoxy atomlinker)-optionally subst. aryl SO₂ phenyl -(1 to 4 linearly linked3-hydroxy isoxazole methoxy atom linker)-optionally subst. heteroarylSO₂ pyridinyl 3-hydroxy isoxazole methoxy SO₂ Pyridinyl CF₃ 3-hydroxyisoxazole methoxy SO₂ Pyridinyl CH₂CF₃ 3-hydroxy isoxazole methoxy SO₂Pyridinyl Halo substituted alkyl 3-hydroxy isoxazole methoxy SO₂Pyridinyl OCH₃ 3-hydroxy isoxazole methoxy SO₂ Pyridinyl OCH₂CH₃3-hydroxy isoxazole methoxy SO₂ Pyridinyl OCH₂CH₂CH₃ 3-hydroxy isoxazolemethoxy SO₂ Pyridinyl OCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole methoxy SO₂Pyridinyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole methoxy SO₂ PyridinylC5-C8 alkoxy 3-hydroxy isoxazole methoxy SO₂ Pyridinyl Halo substitutedalkoxy 3-hydroxy isoxazole methoxy SO₂ Pyridinyl CH₃ 3-hydroxy isoxazolemethoxy SO₂ Pyridinyl CH₂CH₃ 3-hydroxy isoxazole methoxy SO₂ PyridinylCH₂CH₂CH₃ 3-hydroxy isoxazole methoxy SO₂ Pyridinyl CH₂CH₂CH₂CH₃3-hydroxy isoxazole methoxy SO₂ Pyridinyl C5-C8 alkyl 3-hydroxyisoxazole methoxy SO₂ Pyridinyl F 3-hydroxy isoxazole methoxy SO₂Pyridinyl F,F 3-hydroxy isoxazole methoxy SO₂ Pyridinyl F,Cl 3-hydroxyisoxazole methoxy SO₂ Pyridinyl Cl 3-hydroxy isoxazole methoxy SO₂Pyridinyl Cl,Cl 3-hydroxy isoxazole methoxy SO₂ Pyridinyl -(1 to 4linearly linked 3-hydroxy isoxazole methoxy atom linker)-optionallysubst. aryl SO₂ Pyridinyl -(1 to 4 linearly linked 3-hydroxy isoxazolemethoxy atom linker)-optionally subst. heteroaryl CO Phenyl 3-hydroxyisoxazole methoxy CO Phenyl CF₃ 3-hydroxy isoxazole methoxy CO PhenylCH₂CF₃ 3-hydroxy isoxazole methoxy CO Phenyl Halo substituted alkyl3-hydroxy isoxazole methoxy CO Phenyl OCH₃ 3-hydroxy isoxazole methoxyCO Phenyl OCH₂CH₃ 3-hydroxy isoxazole methoxy CO Phenyl OCH₂CH₂CH₃3-hydroxy isoxazole methoxy CO Phenyl OCH₂CH₂CH₂CH₃ 3-hydroxy isoxazolemethoxy CO Phenyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole methoxy CO PhenylC5-C8 alkoxy 3-hydroxy isoxazole methoxy CO Phenyl Halo substitutedalkoxy 3-hydroxy isoxazole methoxy CO Phenyl CH₃ 3-hydroxy isoxazolemethoxy CO Phenyl CH₂CH₃ 3-hydroxy isoxazole methoxy CO Phenyl CH₂CH₂CH₃3-hydroxy isoxazole methoxy CO Phenyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazolemethoxy CO Phenyl C5-C8 alkyl 3-hydroxy isoxazole methoxy CO Phenyl F3-hydroxy isoxazole methoxy CO Phenyl F,F 3-hydroxy isoxazole methoxy COPhenyl F,Cl 3-hydroxy isoxazole methoxy CO Phenyl Cl 3-hydroxy isoxazolemethoxy CO Phenyl Cl,Cl 3-hydroxy isoxazole methoxy CO Phenyl -(1 to 4linearly linked 3-hydroxy isoxazole methoxy atom linker)-optionallysubst. aryl CO Phenyl -(1 to 4 linearly linked 3-hydroxy isoxazolemethoxy atom linker)-optionally subst. heteroaryl CO pyridinyl 3-hydroxyisoxazole methoxy CO Pyridinyl CF₃ 3-hydroxy isoxazole methoxy COPyridinyl CH₂CF₃ 3-hydroxy isoxazole methoxy CO Pyridinyl Halosubstituted alkyl 3-hydroxy isoxazole methoxy CO Pyridinyl OCH₃3-hydroxy isoxazole methoxy CO Pyridinyl OCH₂CH₃ 3-hydroxy isoxazolemethoxy CO Pyridinyl OCH₂CH₂CH₃ 3-hydroxy isoxazole methoxy CO PyridinylOCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole methoxy CO Pyridinyl OCH₂CH₂CH₂CH₂CH₃3-hydroxy isoxazole methoxy CO Pyridinyl C5-C8 alkoxy 3-hydroxyisoxazole methoxy CO Pyridinyl Halo substituted alkoxy 3-hydroxyisoxazole methoxy CO Pyridinyl CH₃ 3-hydroxy isoxazole methoxy COPyridinyl CH₂CH₃ 3-hydroxy isoxazole methoxy CO Pyridinyl CH₂CH₂CH₃3-hydroxy isoxazole methoxy CO Pyridinyl CH₂CH₂CH₂CH₃ 3-hydroxyisoxazole methoxy CO Pyridinyl C5-C8 alkyl 3-hydroxy isoxazole methoxyCO Pyridinyl F 3-hydroxy isoxazole methoxy CO Pyridinyl F,F 3-hydroxyisoxazole methoxy CO Pyridinyl F,Cl 3-hydroxy isoxazole methoxy COPyridinyl Cl 3-hydroxy isoxazole methoxy CO Pyridinyl Cl,Cl 3-hydroxyisoxazole methoxy CO Pyridinyl -(1 to 4 linearly linked 3-hydroxyisoxazole methoxy atom linker)-optionally subst. aryl CO Pyridinyl -(1to 4 linearly linked 3-hydroxy isoxazole methoxy atom linker)-optionallysubst. heteroaryl SO₂ phenyl 3-hydroxy isoxazole ethoxy SO₂ phenyl CF₃3-hydroxy isoxazole ethoxy SO₂ phenyl CH₂CF₃ 3-hydroxy isoxazole ethoxySO₂ phenyl Halo substituted alkyl 3-hydroxy isoxazole ethoxy SO₂ phenylOCH₃ 3-hydroxy isoxazole ethoxy SO₂ phenyl OCH₂CH₃ 3-hydroxy isoxazoleethoxy SO₂ phenyl OCH₂CH₂CH₃ 3-hydroxy isoxazole ethoxy SO₂ phenylOCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole ethoxy SO₂ phenyl OCH₂CH₂CH₂CH₂CH₃3-hydroxy isoxazole ethoxy SO₂ phenyl C5-C8 alkoxy 3-hydroxy isoxazoleethoxy SO₂ phenyl Halo substituted alkoxy 3-hydroxy isoxazole ethoxy SO₂phenyl CH₃ 3-hydroxy isoxazole ethoxy SO₂ phenyl CH₂CH₃ 3-hydroxyisoxazole ethoxy SO₂ phenyl CH₂CH₂CH₃ 3-hydroxy isoxazole ethoxy SO₂phenyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole ethoxy SO₂ phenyl C5-C8 alkyl3-hydroxy isoxazole ethoxy SO₂ phenyl F 3-hydroxy isoxazole ethoxy SO₂phenyl F,F 3-hydroxy isoxazole ethoxy SO₂ phenyl F,Cl 3-hydroxyisoxazole ethoxy SO₂ phenyl Cl 3-hydroxy isoxazole ethoxy SO₂ phenylCl,Cl 3-hydroxy isoxazole ethoxy SO₂ phenyl -(1 to 4 linearly linked3-hydroxy isoxazole ethoxy atom linker)-optionally subst. aryl SO₂phenyl -(1 to 4 linearly linked 3-hydroxy isoxazole ethoxy atomlinker)-optionally subst. heteroaryl SO₂ pyridinyl 3-hydroxy isoxazoleethoxy SO₂ Pyridinyl CF₃ 3-hydroxy isoxazole ethoxy SO₂ Pyridinyl CH₂CF₃3-hydroxy isoxazole ethoxy SO₂ Pyridinyl Halo substituted alkyl3-hydroxy isoxazole ethoxy SO₂ Pyridinyl OCH₃ 3-hydroxy isoxazole ethoxySO₂ Pyridinyl OCH₂CH₃ 3-hydroxy isoxazole ethoxy SO₂ PyridinylOCH₂CH₂CH₃ 3-hydroxy isoxazole ethoxy SO₂ Pyridinyl OCH₂CH₂CH₂CH₃3-hydroxy isoxazole ethoxy SO₂ Pyridinyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxyisoxazole ethoxy SO₂ Pyridinyl C5-C8 alkoxy 3-hydroxy isoxazole ethoxySO₂ Pyridinyl Halo substituted alkoxy 3-hydroxy isoxazole ethoxy SO₂Pyridinyl CH₃ 3-hydroxy isoxazole ethoxy SO₂ Pyridinyl CH₂CH₃ 3-hydroxyisoxazole ethoxy SO₂ Pyridinyl CH₂CH₂CH₃ 3-hydroxy isoxazole ethoxy SO₂Pyridinyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole ethoxy SO₂ Pyridinyl C5-C8alkyl 3-hydroxy isoxazole ethoxy SO₂ Pyridinyl F 3-hydroxy isoxazoleethoxy SO₂ Pyridinyl F,F 3-hydroxy isoxazole ethoxy SO₂ Pyridinyl F,Cl3-hydroxy isoxazole ethoxy SO₂ Pyridinyl Cl 3-hydroxy isoxazole ethoxySO₂ Pyridinyl Cl,Cl 3-hydroxy isoxazole ethoxy SO₂ Pyridinyl -(1 to 4linearly linked 3-hydroxy isoxazole ethoxy atom linker)-optionallysubst. aryl SO₂ Pyridinyl -(1 to 4 linearly linked 3-hydroxy isoxazoleethoxy atom linker)-optionally subst. heteroaryl CO Phenyl 3-hydroxyisoxazole ethoxy CO Phenyl CF₃ 3-hydroxy isoxazole ethoxy CO PhenylCH₂CF₃ 3-hydroxy isoxazole ethoxy CO Phenyl Halo substituted alkyl3-hydroxy isoxazole ethoxy CO Phenyl OCH₃ 3-hydroxy isoxazole ethoxy COPhenyl OCH₂CH₃ 3-hydroxy isoxazole ethoxy CO Phenyl OCH₂CH₂CH₃ 3-hydroxyisoxazole ethoxy CO Phenyl OCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole ethoxy COPhenyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole ethoxy CO Phenyl C5-C8alkoxy 3-hydroxy isoxazole ethoxy CO Phenyl Halo substituted alkoxy3-hydroxy isoxazole ethoxy CO Phenyl CH₃ 3-hydroxy isoxazole ethoxy COPhenyl CH₂CH₃ 3-hydroxy isoxazole ethoxy CO Phenyl CH₂CH₂CH₃ 3-hydroxyisoxazole ethoxy CO Phenyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole ethoxy COPhenyl C5-C8 alkyl 3-hydroxy isoxazole ethoxy CO Phenyl F 3-hydroxyisoxazole ethoxy CO Phenyl F,F 3-hydroxy isoxazole ethoxy CO Phenyl F,Cl3-hydroxy isoxazole ethoxy CO Phenyl Cl 3-hydroxy isoxazole ethoxy COPhenyl Cl,Cl 3-hydroxy isoxazole ethoxy CO Phenyl -(1 to 4 linearlylinked 3-hydroxy isoxazole ethoxy atom linker)-optionally subst. aryl COPhenyl -(1 to 4 linearly linked 3-hydroxy isoxazole ethoxy atomlinker)-optionally subst. heteroaryl CO pyridinyl 3-hydroxy isoxazoleethoxy CO Pyridinyl CF₃ 3-hydroxy isoxazole ethoxy CO Pyridinyl CH₂CF₃3-hydroxy isoxazole ethoxy CO Pyridinyl Halo substituted alkyl 3-hydroxyisoxazole ethoxy CO Pyridinyl OCH₃ 3-hydroxy isoxazole ethoxy COPyridinyl OCH₂CH₃ 3-hydroxy isoxazole ethoxy CO Pyridinyl OCH₂CH₂CH₃3-hydroxy isoxazole ethoxy CO Pyridinyl OCH₂CH₂CH₂CH₃ 3-hydroxyisoxazole ethoxy CO Pyridinyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazoleethoxy CO Pyridinyl C5-C8 alkoxy 3-hydroxy isoxazole ethoxy CO PyridinylHalo substituted alkoxy 3-hydroxy isoxazole ethoxy CO Pyridinyl CH₃3-hydroxy isoxazole ethoxy CO Pyridinyl CH₂CH₃ 3-hydroxy isoxazoleethoxy CO Pyridinyl CH₂CH₂CH₃ 3-hydroxy isoxazole ethoxy CO PyridinylCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole ethoxy CO Pyridinyl C5-C8 alkyl3-hydroxy isoxazole ethoxy CO Pyridinyl F 3-hydroxy isoxazole ethoxy COPyridinyl F,F 3-hydroxy isoxazole ethoxy CO Pyridinyl F,Cl 3-hydroxyisoxazole ethoxy CO Pyridinyl Cl 3-hydroxy isoxazole ethoxy CO PyridinylCl,Cl 3-hydroxy isoxazole ethoxy CO Pyridinyl -(1 to 4 linearly linked3-hydroxy isoxazole ethoxy atom linker)-optionally subst. aryl COPyridinyl -(1 to 4 linearly linked 3-hydroxy isoxazole ethoxy atomlinker)-optionally subst. heteroaryl SO₂ phenyl 3-hydroxy isoxazolepropoxy SO₂ phenyl CF₃ 3-hydroxy isoxazole propoxy SO₂ phenyl CH₂CF₃3-hydroxy isoxazole propoxy SO₂ phenyl Halo substituted alkyl 3-hydroxyisoxazole propoxy SO₂ phenyl OCH₃ 3-hydroxy isoxazole propoxy SO₂ phenylOCH₂CH₃ 3-hydroxy isoxazole propoxy SO₂ phenyl OCH₂CH₂CH₃ 3-hydroxyisoxazole propoxy SO₂ phenyl OCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole propoxySO₂ phenyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole propoxy SO₂ phenyl C5-C8alkoxy 3-hydroxy isoxazole propoxy SO₂ phenyl Halo substituted alkoxy3-hydroxy isoxazole propoxy SO₂ phenyl CH₃ 3-hydroxy isoxazole propoxySO₂ phenyl CH₂CH₃ 3-hydroxy isoxazole propoxy SO₂ phenyl CH₂CH₂CH₃3-hydroxy isoxazole propoxy SO₂ phenyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazolepropoxy SO₂ phenyl C5-C8 alkyl 3-hydroxy isoxazole propoxy SO₂ phenyl F3-hydroxy isoxazole propoxy SO₂ phenyl F,F 3-hydroxy isoxazole propoxySO₂ phenyl F,Cl 3-hydroxy isoxazole propoxy SO₂ phenyl Cl 3-hydroxyisoxazole propoxy SO₂ phenyl Cl,Cl 3-hydroxy isoxazole propoxy SO₂phenyl -(1 to 4 linearly linked 3-hydroxy isoxazole propoxy atomlinker)-optionally subst. aryl SO₂ phenyl -(1 to 4 linearly linked3-hydroxy isoxazole propoxy atom linker)-optionally subst. heteroarylSO₂ pyridinyl 3-hydroxy isoxazole propoxy SO₂ Pyridinyl CF₃ 3-hydroxyisoxazole propoxy SO₂ Pyridinyl CH₂CF₃ 3-hydroxy isoxazole propoxy SO₂Pyridinyl Halo substituted alkyl 3-hydroxy isoxazole propoxy SO₂Pyridinyl OCH₃ 3-hydroxy isoxazole propoxy SO₂ Pyridinyl OCH₂CH₃3-hydroxy isoxazole propoxy SO₂ Pyridinyl OCH₂CH₂CH₃ 3-hydroxy isoxazolepropoxy SO₂ Pyridinyl OCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole propoxy SO₂Pyridinyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole propoxy SO₂ PyridinylC5-C8 alkoxy 3-hydroxy isoxazole propoxy SO₂ Pyridinyl Halo substitutedalkoxy 3-hydroxy isoxazole propoxy SO₂ Pyridinyl CH₃ 3-hydroxy isoxazolepropoxy SO₂ Pyridinyl CH₂CH₃ 3-hydroxy isoxazole propoxy SO₂ PyridinylCH₂CH₂CH₃ 3-hydroxy isoxazole propoxy SO₂ Pyridinyl CH₂CH₂CH₂CH₃3-hydroxy isoxazole propoxy SO₂ Pyridinyl C5-C8 alkyl 3-hydroxyisoxazole propoxy SO₂ Pyridinyl F 3-hydroxy isoxazole propoxy SO₂Pyridinyl F,F 3-hydroxy isoxazole propoxy SO₂ Pyridinyl F,Cl 3-hydroxyisoxazole propoxy SO₂ Pyridinyl Cl 3-hydroxy isoxazole propoxy SO₂Pyridinyl Cl,Cl 3-hydroxy isoxazole propoxy SO₂ Pyridinyl -(1 to 4linearly linked 3-hydroxy isoxazole propoxy atom linker)-optionallysubst. aryl SO₂ Pyridinyl -(1 to 4 linearly linked 3-hydroxy isoxazolepropoxy atom linker)-optionally subst. heteroaryl CO Phenyl 3-hydroxyisoxazole propoxy CO Phenyl CF₃ 3-hydroxy isoxazole propoxy CO PhenylCH₂CF₃ 3-hydroxy isoxazole propoxy CO Phenyl Halo substituted alkyl3-hydroxy isoxazole propoxy CO Phenyl OCH₃ 3-hydroxy isoxazole propoxyCO Phenyl OCH₂CH₃ 3-hydroxy isoxazole propoxy CO Phenyl OCH₂CH₂CH₃3-hydroxy isoxazole propoxy CO Phenyl OCH₂CH₂CH₂CH₃ 3-hydroxy isoxazolepropoxy CO Phenyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole propoxy CO PhenylC5-C8 alkoxy 3-hydroxy isoxazole propoxy CO Phenyl Halo substitutedalkoxy 3-hydroxy isoxazole propoxy CO Phenyl CH₃ 3-hydroxy isoxazolepropoxy CO Phenyl CH₂CH₃ 3-hydroxy isoxazole propoxy CO Phenyl CH₂CH₂CH₃3-hydroxy isoxazole propoxy CO Phenyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazolepropoxy CO Phenyl C5-C8 alkyl 3-hydroxy isoxazole propoxy CO Phenyl F3-hydroxy isoxazole propoxy CO Phenyl F,F 3-hydroxy isoxazole propoxy COPhenyl F,Cl 3-hydroxy isoxazole propoxy CO Phenyl Cl 3-hydroxy isoxazolepropoxy CO Phenyl Cl,Cl 3-hydroxy isoxazole propoxy CO Phenyl -(1 to 4linearly linked 3-hydroxy isoxazole propoxy atom linker)-optionallysubst. aryl CO Phenyl -(1 to 4 linearly linked 3-hydroxy isoxazolepropoxy atom linker)-optionally subst. heteroaryl CO pyridinyl 3-hydroxyisoxazole propoxy CO Pyridinyl CF₃ 3-hydroxy isoxazole propoxy COPyridinyl CH₂CF₃ 3-hydroxy isoxazole propoxy CO Pyridinyl Halosubstituted alkyl 3-hydroxy isoxazole propoxy CO Pyridinyl OCH₃3-hydroxy isoxazole propoxy CO Pyridinyl OCH₂CH₃ 3-hydroxy isoxazolepropoxy CO Pyridinyl OCH₂CH₂CH₃ 3-hydroxy isoxazole propoxy CO PyridinylOCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole propoxy CO Pyridinyl OCH₂CH₂CH₂CH₂CH₃3-hydroxy isoxazole propoxy CO Pyridinyl C5-C8 alkoxy 3-hydroxyisoxazole propoxy CO Pyridinyl Halo substituted alkoxy 3-hydroxyisoxazole propoxy CO Pyridinyl CH₃ 3-hydroxy isoxazole propoxy COPyridinyl CH₂CH₃ 3-hydroxy isoxazole propoxy CO Pyridinyl CH₂CH₂CH₃3-hydroxy isoxazole propoxy CO Pyridinyl CH₂CH₂CH₂CH₃ 3-hydroxyisoxazole propoxy CO Pyridinyl C5-C8 alkyl 3-hydroxy isoxazole propoxyCO Pyridinyl F 3-hydroxy isoxazole propoxy CO Pyridinyl F,F 3-hydroxyisoxazole propoxy CO Pyridinyl F,Cl 3-hydroxy isoxazole propoxy COPyridinyl Cl 3-hydroxy isoxazole propoxy CO Pyridinyl Cl,Cl 3-hydroxyisoxazole propoxy CO Pyridinyl -(1 to 4 linearly linked 3-hydroxyisoxazole propoxy atom linker)-optionally subst. aryl CO Pyridinyl -(1to 4 linearly linked 3-hydroxy isoxazole propoxy atom linker)-optionallysubst. heteroaryl SO₂ phenyl 3-hydroxy isoxazole —SCH₃ SO₂ phenyl CF₃3-hydroxy isoxazole —SCH₃ SO₂ phenyl CH₂CF₃ 3-hydroxy isoxazole —SCH₃SO₂ phenyl Halo substituted alkyl 3-hydroxy isoxazole —SCH₃ SO₂ phenylOCH₃ 3-hydroxy isoxazole —SCH₃ SO₂ phenyl OCH₂CH₃ 3-hydroxy isoxazole—SCH₃ SO₂ phenyl OCH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₃ SO₂ phenylOCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₃ SO₂ phenyl OCH₂CH₂CH₂CH₂CH₃3-hydroxy isoxazole —SCH₃ SO₂ phenyl C5-C8 alkoxy 3-hydroxy isoxazole—SCH₃ SO₂ phenyl Halo substituted alkoxy 3-hydroxy isoxazole —SCH₃ SO₂phenyl CH₃ 3-hydroxy isoxazole —SCH₃ SO₂ phenyl CH₂CH₃ 3-hydroxyisoxazole —SCH₃ SO₂ phenyl CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₃ SO₂phenyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₃ SO₂ phenyl C5-C8 alkyl3-hydroxy isoxazole —SCH₃ SO₂ phenyl F 3-hydroxy isoxazole —SCH₃ SO₂phenyl F,F 3-hydroxy isoxazole —SCH₃ SO₂ phenyl F,Cl 3-hydroxy isoxazole—SCH₃ SO₂ phenyl Cl 3-hydroxy isoxazole —SCH₃ SO₂ phenyl Cl,Cl 3-hydroxyisoxazole —SCH₃ SO₂ phenyl -(1 to 4 linearly linked 3-hydroxy isoxazole—SCH₃ atom linker)-optionally subst. aryl SO₂ phenyl -(1 to 4 linearlylinked 3-hydroxy isoxazole —SCH₃ atom linker)-optionally subst.heteroaryl SO₂ pyridinyl 3-hydroxy isoxazole —SCH₃ SO₂ Pyridinyl CF₃3-hydroxy isoxazole —SCH₃ SO₂ Pyridinyl CH₂CF₃ 3-hydroxy isoxazole —SCH₃SO₂ Pyridinyl Halo substituted alkyl 3-hydroxy isoxazole —SCH₃ SO₂Pyridinyl OCH₃ 3-hydroxy isoxazole —SCH₃ SO₂ Pyridinyl OCH₂CH₃ 3-hydroxyisoxazole —SCH₃ SO₂ Pyridinyl OCH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₃ SO₂Pyridinyl OCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₃ SO₂ PyridinylOCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₃ SO₂ Pyridinyl C5-C8 alkoxy3-hydroxy isoxazole —SCH₃ SO₂ Pyridinyl Halo substituted alkoxy3-hydroxy isoxazole —SCH₃ SO₂ Pyridinyl CH₃ 3-hydroxy isoxazole —SCH₃SO₂ Pyridinyl CH₂CH₃ 3-hydroxy isoxazole —SCH₃ SO₂ Pyridinyl CH₂CH₂CH₃3-hydroxy isoxazole —SCH₃ SO₂ Pyridinyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole—SCH₃ SO₂ Pyridinyl C5-C8 alkyl 3-hydroxy isoxazole —SCH₃ SO₂ PyridinylF 3-hydroxy isoxazole —SCH₃ SO₂ Pyridinyl F,F 3-hydroxy isoxazole —SCH₃SO₂ Pyridinyl F,Cl 3-hydroxy isoxazole —SCH₃ SO₂ Pyridinyl Cl 3-hydroxyisoxazole —SCH₃ SO₂ Pyridinyl Cl,Cl 3-hydroxy isoxazole —SCH₃ SO₂Pyridinyl -(1 to 4 linearly linked 3-hydroxy isoxazole —SCH₃ atomlinker)-optionally subst. aryl SO₂ Pyridinyl -(1 to 4 linearly linked3-hydroxy isoxazole —SCH₃ atom linker)-optionally subst. heteroaryl COPhenyl 3-hydroxy isoxazole —SCH₃ CO Phenyl CF₃ 3-hydroxy isoxazole —SCH₃CO Phenyl CH₂CF₃ 3-hydroxy isoxazole —SCH₃ CO Phenyl Halo substitutedalkyl 3-hydroxy isoxazole —SCH₃ CO Phenyl OCH₃ 3-hydroxy isoxazole —SCH₃CO Phenyl OCH₂CH₃ 3-hydroxy isoxazole —SCH₃ CO Phenyl OCH₂CH₂CH₃3-hydroxy isoxazole —SCH₃ CO Phenyl OCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole—SCH₃ CO Phenyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₃ CO PhenylC5-C8 alkoxy 3-hydroxy isoxazole —SCH₃ CO Phenyl Halo substituted alkoxy3-hydroxy isoxazole —SCH₃ CO Phenyl CH₃ 3-hydroxy isoxazole —SCH₃ COPhenyl CH₂CH₃ 3-hydroxy isoxazole —SCH₃ CO Phenyl CH₂CH₂CH₃ 3-hydroxyisoxazole —SCH₃ CO Phenyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₃ COPhenyl C5-C8 alkyl 3-hydroxy isoxazole —SCH₃ CO Phenyl F 3-hydroxyisoxazole —SCH₃ CO Phenyl F,F 3-hydroxy isoxazole —SCH₃ CO Phenyl F,Cl3-hydroxy isoxazole —SCH₃ CO Phenyl Cl 3-hydroxy isoxazole —SCH₃ COPhenyl Cl,Cl 3-hydroxy isoxazole —SCH₃ CO Phenyl -(1 to 4 linearlylinked 3-hydroxy isoxazole —SCH₃ atom linker)-optionally subst. aryl COPhenyl -(1 to 4 linearly linked 3-hydroxy isoxazole —SCH₃ atomlinker)-optionally subst. heteroaryl CO pyridinyl 3-hydroxy isoxazole—SCH₃ CO Pyridinyl CF₃ 3-hydroxy isoxazole —SCH₃ CO Pyridinyl CH₂CF₃3-hydroxy isoxazole —SCH₃ CO Pyridinyl Halo substituted alkyl 3-hydroxyisoxazole —SCH₃ CO Pyridinyl OCH₃ 3-hydroxy isoxazole —SCH₃ CO PyridinylOCH₂CH₃ 3-hydroxy isoxazole —SCH₃ CO Pyridinyl OCH₂CH₂CH₃ 3-hydroxyisoxazole —SCH₃ CO Pyridinyl OCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₃ COPyridinyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₃ CO Pyridinyl C5-C8alkoxy 3-hydroxy isoxazole —SCH₃ CO Pyridinyl Halo substituted alkoxy3-hydroxy isoxazole —SCH₃ CO Pyridinyl CH₃ 3-hydroxy isoxazole —SCH₃ COPyridinyl CH₂CH₃ 3-hydroxy isoxazole —SCH₃ CO Pyridinyl CH₂CH₂CH₃3-hydroxy isoxazole —SCH₃ CO Pyridinyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole—SCH₃ CO Pyridinyl C5-C8 alkyl 3-hydroxy isoxazole —SCH₃ CO Pyridinyl F3-hydroxy isoxazole —SCH₃ CO Pyridinyl F,F 3-hydroxy isoxazole —SCH₃ COPyridinyl F,Cl 3-hydroxy isoxazole —SCH₃ CO Pyridinyl Cl 3-hydroxyisoxazole —SCH₃ CO Pyridinyl Cl,Cl 3-hydroxy isoxazole —SCH₃ COPyridinyl -(1 to 4 linearly linked 3-hydroxy isoxazole —SCH₃ atomlinker)-optionally subst. aryl CO Pyridinyl -(1 to 4 linearly linked3-hydroxy isoxazole —SCH₃ atom linker)-optionally subst. heteroaryl SO₂phenyl 3-hydroxy isoxazole —SCH₂CH₃ SO₂ phenyl CF₃ 3-hydroxy isoxazole—SCH₂CH₃ SO₂ phenyl CH₂CF₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂ phenyl Halosubstituted alkyl 3-hydroxy isoxazole —SCH₂CH₃ SO₂ phenyl OCH₃ 3-hydroxyisoxazole —SCH₂CH₃ SO₂ phenyl OCH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂phenyl OCH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂ phenyl OCH₂CH₂CH₂CH₃3-hydroxy isoxazole —SCH₂CH₃ SO₂ phenyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxyisoxazole —SCH₂CH₃ SO₂ phenyl C5-C8 alkoxy 3-hydroxy isoxazole —SCH₂CH₃SO₂ phenyl Halo substituted alkoxy 3-hydroxy isoxazole —SCH₂CH₃ SO₂phenyl CH₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂ phenyl CH₂CH₃ 3-hydroxyisoxazole —SCH₂CH₃ SO₂ phenyl CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂phenyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂ phenyl C5-C8 alkyl3-hydroxy isoxazole —SCH₂CH₃ SO₂ phenyl F 3-hydroxy isoxazole —SCH₂CH₃SO₂ phenyl F,F 3-hydroxy isoxazole —SCH₂CH₃ SO₂ phenyl F,Cl 3-hydroxyisoxazole —SCH₂CH₃ SO₂ phenyl Cl 3-hydroxy isoxazole —SCH₂CH₃ SO₂ phenylCl,Cl 3-hydroxy isoxazole —SCH₂CH₃ SO₂ phenyl -(1 to 4 linearly linked3-hydroxy isoxazole —SCH₂CH₃ atom linker)-optionally subst. aryl SO₂phenyl -(1 to 4 linearly linked 3-hydroxy isoxazole —SCH₂CH₃ atomlinker)-optionally subst. heteroaryl SO₂ pyridinyl 3-hydroxy isoxazole—SCH₂CH₃ SO₂ Pyridinyl CF₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂ PyridinylCH₂CF₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂ Pyridinyl Halo substituted alkyl3-hydroxy isoxazole —SCH₂CH₃ SO₂ Pyridinyl OCH₃ 3-hydroxy isoxazole—SCH₂CH₃ SO₂ Pyridinyl OCH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂Pyridinyl OCH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂ PyridinylOCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂ PyridinylOCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂ Pyridinyl C5-C8 alkoxy3-hydroxy isoxazole —SCH₂CH₃ SO₂ Pyridinyl Halo substituted alkoxy3-hydroxy isoxazole —SCH₂CH₃ SO₂ Pyridinyl CH₃ 3-hydroxy isoxazole—SCH₂CH₃ SO₂ Pyridinyl CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂ PyridinylCH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ SO₂ Pyridinyl CH₂CH₂CH₂CH₃3-hydroxy isoxazole —SCH₂CH₃ SO₂ Pyridinyl C5-C8 alkyl 3-hydroxyisoxazole —SCH₂CH₃ SO₂ Pyridinyl F 3-hydroxy isoxazole —SCH₂CH₃ SO₂Pyridinyl F,F 3-hydroxy isoxazole —SCH₂CH₃ SO₂ Pyridinyl F,Cl 3-hydroxyisoxazole —SCH₂CH₃ SO₂ Pyridinyl Cl 3-hydroxy isoxazole —SCH₂CH₃ SO₂Pyridinyl Cl,Cl 3-hydroxy isoxazole —SCH₂CH₃ SO₂ Pyridinyl -(1 to 4linearly linked 3-hydroxy isoxazole —SCH₂CH₃ atom linker)-optionallysubst. aryl SO₂ Pyridinyl -(1 to 4 linearly linked 3-hydroxy isoxazole—SCH₂CH₃ atom linker)-optionally subst. heteroaryl CO Phenyl 3-hydroxyisoxazole —SCH₂CH₃ CO Phenyl CF₃ 3-hydroxy isoxazole —SCH₂CH₃ CO PhenylCH₂CF₃ 3-hydroxy isoxazole —SCH₂CH₃ CO Phenyl Halo substituted alkyl3-hydroxy isoxazole —SCH₂CH₃ CO Phenyl OCH₃ 3-hydroxy isoxazole —SCH₂CH₃CO Phenyl OCH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ CO Phenyl OCH₂CH₂CH₃3-hydroxy isoxazole —SCH₂CH₃ CO Phenyl OCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole—SCH₂CH₃ CO Phenyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ COPhenyl C5-C8 alkoxy 3-hydroxy isoxazole —SCH₂CH₃ CO Phenyl Halosubstituted alkoxy 3-hydroxy isoxazole —SCH₂CH₃ CO Phenyl CH₃ 3-hydroxyisoxazole —SCH₂CH₃ CO Phenyl CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ COPhenyl CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ CO Phenyl CH₂CH₂CH₂CH₃3-hydroxy isoxazole —SCH₂CH₃ CO Phenyl C5-C8 alkyl 3-hydroxy isoxazole—SCH₂CH₃ CO Phenyl F 3-hydroxy isoxazole —SCH₂CH₃ CO Phenyl F,F3-hydroxy isoxazole —SCH₂CH₃ CO Phenyl F,Cl 3-hydroxy isoxazole —SCH₂CH₃CO Phenyl Cl 3-hydroxy isoxazole —SCH₂CH₃ CO Phenyl Cl,Cl 3-hydroxyisoxazole —SCH₂CH₃ CO Phenyl -(1 to 4 linearly linked 3-hydroxyisoxazole —SCH₂CH₃ atom linker)-optionally subst. aryl CO Phenyl -(1 to4 linearly linked 3-hydroxy isoxazole —SCH₂CH₃ atom linker)-optionallysubst. heteroaryl CO pyridinyl 3-hydroxy isoxazole —SCH₂CH₃ CO PyridinylCF₃ 3-hydroxy isoxazole —SCH₂CH₃ CO Pyridinyl CH₂CF₃ 3-hydroxy isoxazole—SCH₂CH₃ CO Pyridinyl Halo substituted alkyl 3-hydroxy isoxazole—SCH₂CH₃ CO Pyridinyl OCH₃ 3-hydroxy isoxazole —SCH₂CH₃ CO PyridinylOCH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ CO Pyridinyl OCH₂CH₂CH₃ 3-hydroxyisoxazole —SCH₂CH₃ CO Pyridinyl OCH₂CH₂CH₂CH₃ 3-hydroxy isoxazole—SCH₂CH₃ CO Pyridinyl OCH₂CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ COPyridinyl C5-C8 alkoxy 3-hydroxy isoxazole —SCH₂CH₃ CO Pyridinyl Halosubstituted alkoxy 3-hydroxy isoxazole —SCH₂CH₃ CO Pyridinyl CH₃3-hydroxy isoxazole —SCH₂CH₃ CO Pyridinyl CH₂CH₃ 3-hydroxy isoxazole—SCH₂CH₃ CO Pyridinyl CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ COPyridinyl CH₂CH₂CH₂CH₃ 3-hydroxy isoxazole —SCH₂CH₃ CO Pyridinyl C5-C8alkyl 3-hydroxy isoxazole —SCH₂CH₃ CO Pyridinyl F 3-hydroxy isoxazole—SCH₂CH₃ CO Pyridinyl F,F 3-hydroxy isoxazole —SCH₂CH₃ CO Pyridinyl F,Cl3-hydroxy isoxazole —SCH₂CH₃ CO Pyridinyl Cl 3-hydroxy isoxazole—SCH₂CH₃ CO Pyridinyl Cl,Cl 3-hydroxy isoxazole —SCH₂CH₃ CO Pyridinyl-(1 to 4 linearly linked 3-hydroxy isoxazole —SCH₂CH₃ atomlinker)-optionally subst. aryl CO Pyridinyl -(1 to 4 linearly linked3-hydroxy isoxazole —SCH₂CH₃ atom linker)-optionally subst. heteroaryl

With reference to the compounds described in Table 4 (and for each ofthe bicyclic cores), additional compounds are described for each of thesubstitutent combinations therein where the substituent shown in Table 4at the 5-position is instead an aryl group; a heteroaryl group; amonocyclic aryl group; a monocyclic heteroaryl group; a bicyclic arylgroup; a bicyclic heteroaryl group; a substituted aryl group; asubstituted heteroaryl group; a pyridinyl group; a pyrimidinyl group; apyradazinyl group; a pyrrolyl group; a thiophenyl group.

With reference to the compounds described in Table 4 and the precedingparagraph, additional compounds are described in which L is CH₂.

With reference to the compounds described in Table 4 and the precedingtwo paragraphs, additional compounds are described in which the moiety Ais an acyl sulphonamide (—C(═O)—N—SO₂CH₃).

All patents and other references cited in the specification areindicative of the level of skill of those skilled in the art to whichthe invention pertains, and are incorporated by reference in theirentireties, including any tables and figures, to the same extent as ifeach reference had been incorporated by reference in its entiretyindividually.

One skilled in the art would readily appreciate that the presentinvention is well adapted to obtain the ends and advantages mentioned,as well as those inherent therein. The methods, variances, andcompositions described herein as presently representative of preferredembodiments are exemplary and are not intended as limitations on thescope of the invention. Changes therein and other uses will occur tothose skilled in the art, which are encompassed within the spirit of theinvention, are defined by the scope of the claims.

It will be readily apparent to one skilled in the art that varyingsubstitutions and modifications may be made to the invention disclosedherein without departing from the scope and spirit of the invention. Forexample, variations can be made to exemplary compounds of Formula Itoprovide additional active compounds. Thus, such additional embodimentsare within the scope of the present invention and the following claims.

The invention illustratively described herein suitably may be practicedin the absence of any element or elements, limitation or limitationswhich is not specifically disclosed herein. Thus, for example, in eachinstance herein any of the terms “comprising”, “consisting essentiallyof” and “consisting of” may be replaced with either of the other twoterms. The terms and expressions which have been employed are used asterms of description and not of limitation, and there is no intentionthat in the use of such terms and expressions of excluding anyequivalents of the features shown and described or portions thereof, butit is recognized that various modifications are possible within thescope of the invention claimed. Thus, it should be understood thatalthough the present invention has been specifically disclosed bypreferred embodiments and optional features, modification and variationof the concepts herein disclosed may be resorted to by those skilled inthe art, and that such modifications and variations are considered to bewithin the scope of this invention as defined by the appended claims.

In addition, where features or aspects of the invention are described interms of Markush groups or other grouping of alternatives, those skilledin the art will recognize that the invention is also thereby describedin terms of any individual member or subgroup of members of the Markushgroup or other group.

Also, unless indicated to the contrary, where various numerical valuesare provided for embodiments, additional embodiments are described bytaking any 2 different values as the endpoints of a range. Such rangesare also within the scope of the described invention.

Thus, additional embodiments are within the scope of the invention andwithin the following claims.

1. A method for developing an improved modulator active on a PPAR,comprising determining whether any of a plurality of test compoundshaving the chemical structure of Formula I, namely

wherein U, V, W, X, and Y are independently N or CR⁸, where there are nomore than 4 nitrogens in the bicyclic ring structure shown in Formula I,and there are no more than 2 nitrogens in either of the rings of saidbicyclic ring structure; R¹ is a carboxyl group or ester thereof or acarboxylic acid isostere; R² is hydrogen, optionally substituted loweralkyl, —CH₂—CR¹²═CR¹³R¹⁴, —CH₂—C≡CR¹⁵, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, optionally substituted heteroaralkyl, —C(Z)NR¹⁰R¹¹,—C(Z)R²⁰, —S(O)₂NR¹⁰R¹¹; or S(O)₂R²¹; R⁶ and R⁷ are independentlyhydrogen, optionally substituted lower alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, or optionally substituted heteroaralkyl, or R⁶ and R⁷combine to form a mono-carbocyclic or mono-heterocyclic 5- or 6-memberedring system; R⁸ is hydrogen, halo, optionally substituted lower alkyl,—CH₂—CR¹²═CR¹³R¹⁴, optionally substituted cycloalkyl, optionallysubstituted monofluoroalkyl, optionally substituted difluoroalkyl,optionally substituted trifluoroalkyl, trifluoromethyl, —CH₂—C≡CR¹⁵,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heteroaryl,optionally substituted heteroaralkyl, —OR⁹, —SR⁹, —NR¹⁰R¹¹,—C(Z)NR¹⁰R¹¹, —C(Z)R²⁰, —S(O)₂NR¹⁰R¹¹, or —S(O)₂R²¹; R⁹ is optionallysubstituted lower alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted heteroaryl, or optionallysubstituted heteroaralkyl; R¹⁰ and R¹¹ are independently hydrogen,optionally substituted lower alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heteroaryl, oroptionally substituted heteroaralkyl, or R¹⁰ and R¹¹ combine to form amono-carbocyclic or mono-heterocyclic 5- or 6-membered ring system; R¹²,R¹³, R¹⁴, and R¹⁵ are independently optionally substituted lower alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, or optionally substitutedheteroaralkyl; R²⁰ is optionally substituted monofluoroalkyl,trifluoromethyl, optionally substituted difluoroalkyl,—CH₂—CR¹²═CR¹³R¹⁴, —CH₂—C≡CR¹⁵, optionally substituted lower alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, or optionally substitutedheteroaralkyl; R²¹ is optionally substituted lower alkoxy,—CH₂—CR¹²═CR¹³R¹⁴, —CH₂—C≡CR¹⁵, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heteroaryl, oroptionally substituted heteroaralkyl; Z is O or S; and n=0, 1, or 2,wherein said compound is different from3-(5-methoxy-1-p-toluenesulfonylindol-3-yl)propionic acid and1-(2,4,6-triisopropylphenylsulfonyl)indole-3-propionic acid provides animprovement in one or more desired pharmacologic properties relative toa reference compound active on said PPAR; and selecting thosecompound(s) if any, that have an improvement in said desiredpharmacologic property, thereby providing an improved modulator.
 2. Amethod of designing a ligand that binds to at least one member of thePPAR protein family, comprising identifying as molecular scaffolds oneor more compounds that bind to a binding site of a PPAR with lowaffinity; determining the orientation of the one or more molecularscaffolds at the binding site of the PPAR by obtaining co-crystalstructures of the molecular scaffolds in the binding site; andidentifying one or more structures of at least one scaffold moleculethat, when modified, provide a ligand having altered binding affinity orbinding specificity or both for binding to the PPAR as compared to thebinding of the scaffold molecule.
 3. The method of claim 2, furthercomprising isolating co-crystals of the molecular scaffolds bound to thePPAR, and determining the orientation of the molecular scaffold byperforming X-ray crystallography on the co-crystals.
 4. The method ofclaim 2, wherein the plurality of distinct compounds are each assayedfor binding to a plurality of members of the PPAR family.
 5. A method ofdesigning a ligand that binds to at least one PPAR that is a member ofthe PPAR family, comprising, identifying as molecular scaffolds one ormore compounds that bind to binding sites of a plurality of members ofthe PPAR family; determining the orientation of the one or moremolecular scaffolds at the binding site of the PPAR to identifychemically tractable structures of the scaffolds that, when modified,alter the binding affinity or binding specificity between the scaffoldand the PPAR; synthesizing a ligand wherein one or more of thechemically tractable structures of the molecular scaffold is modified toprovide a ligand that binds to the PPAR with altered binding affinity orbinding specificity.
 6. The method of claim 5, further comprisingisolating co-crystals of the molecular scaffolds bound to the PPAR, anddetermining the orientation of a molecular scaffolds at the binding siteof the protein by performing X-ray crystallography on the co-crystals.7. The method of claim 5, wherein a plurality of distinct compounds areeach assayed for binding to a plurality of members of the PPAR family.8. A method for identifying binding characteristics of a ligand of aPPAR, comprising identifying at least one conserved interacting residuein said PPAR that interacts with at least two binding molecules; andidentifying at least one common interaction property of said at leasttwo binding molecules with said conserved residue, thereby identifyingat least one said characteristic.
 9. A method for identifyingenergetically allowed sites on a PPAR binding compound for attachment ofan additional component, comprising analyzing the orientation of saidbinding compound in a PPAR binding site, thereby identifying accessiblesites on said compound of said additional component.
 10. The method ofclaim 9, further comprising calculating the free energy cost ofattachment of said additional component at one or more of saidaccessible sites.
 11. The method of claim 9, wherein said orientation isdetermined by co-crystallography.
 12. A method for attaching a PPARbinding compound to an attachment component at an energentically allowedsite, comprising identifying energetically allowed sites for attachmentof a said attachment component on a binding compound; and attaching saidcompound or derivative thereof to said attachment component at saidenergetically allowed site.
 13. A method for making an affinity matrixcomprising a PPAR binding compound, comprising identifying energeticallyallowed sites on a PPAR binding compound for attachment to a solid phasematrix; and attaching said PPAR binding compound to said solid phasematrix through a said energetically allowed site.